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RH02061-201131 CSR

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Report Study Number RH02061 (201133)

Study Title A randomised, double-blind, study to investigate the effects of creatine supplementation on muscle energetics and cognitive function in young healthy male athletes and an ageing population using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and functional magnetic resonance imaging (fMRI)

Test Product Creatine

Indication Nutritional

Phase Exploratory

Investigator Name: Frans van den Berg MBChB

Affiliation Address: The HMR Analytical Laboratory Hammersmith Medicines Research Ltd Cumberland Avenue London NW10 7EW

Study Initiation (first subject/first visit):

17 Dec 2013

Study Completion: 24 Jun 2014

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Document Name RH02061-201131 CSR Type Version Document Identifier Effective Date eldo_controlled 0.1; CURRENT; In Progress; Most-Recent 090032d580a5e8a0 Reason For Issue

Synopsis RH02061 201131 CSR

List of Abbreviations Ethics

Table of Contents

Page 7 17 17 18

Investigators and Study Administrative Structure 19 1 Introduction 20 2 Study Objectives 21

2.1 Primary Objective 21 2.2 Secondary Objectives 21 2.3 Exploratory Objective 21

3 Investigational Plan 21 3.1 Overall Study Design and Plan Description 21

3.1.1 Study visits 22 3.1.2 Study assessments 22

3.2 Discussion of Study Design, including the Choice of Control Groups 23 3.3 Selection of Study Population 23

3.3.1 Inclusion criteria 23 3.3.2 Exclusion criteria 24 3.3.3 Subject restrictions 26 3.3.4 Removal of subjects from therapy or assessment 27

3.4 Treatments 27 3.4.1 Treatments administered 27 3.4.2 Identity of investigational products 27 3.4.3 Treatment assignment 27 3.4.4 Selection of doses in the study 28 3.4.5 Selection and timing of dose for each subject 28 3.4.6 Blinding 28 3.4.7 Treatment compliance 28

3.5 Demographic, Efficacy and Safety Variables and Schedule of Study Events 29 3.5.1 Schedule of study events 29 3.5.2 Screening methods, measurements and evaluations 32 3.5.3 Efficacy measurements and evaluations 33 3.5.4 Structured exercise programme 35 3.5.5 Safety measurements and evaluations 35 3.5.6 MRI questionnaire 38 3.5.7 Urine and breath tests 38 3.5.8 Height and weight 38 3.5.9 Appropriateness of measurements 38 3.5.10 Primary efficacy variable 39 3.5.11 Drug concentration measurements 39 3.5.12 Changes in the conduct of the study 39

3.6 Data Quality Assurance 39 3.7 Data Analysis Methods 39

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3.7.1 Determination of sample size 3.7.2 General considerations for data analysis 3.7.3 Study populations 3.7.4 Efficacy analysis and statistical methods 3.7.5 Safety parameters 3.7.6 Changes in the planned analyses

4 Study Subjects 4.1 Disposition of Subjects 4.2 Protocol Deviations 4.3 Data Sets Analysed 4.4 Demographic and Other Baseline Characteristics

4.4.1 Demographics 4.4.2 Current medical disorders and medical history

4.5 Concomitant Medications 4.6 Compliance

5 Efficacy Results 5.1 Primary Efficacy Parameters 5.2 Secondary Efficacy Parameters

5.2.1 Imaging Parameters 5.2.2 Cognitive Parameters 5.2.3. Exploratory Efficacy Parameters

5.3 Tabulation of Individual Response Data 5.4 Efficacy Conclusions

5.4.1 Primary efficacy parameters 5.4.2 Secondary efficacy parameters

6 Safety Evaluation 6.1 Extent of Exposure 6.2 Adverse Events (AEs)

6.2.1 Brief summary of adverse events 6.2.2 Display of adverse events 6.2.3 Analysis of adverse events 6.2.4 Listing of adverse events by subject

6.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 6.4 Safety Conclusions

7 Discussion and Overall Conclusions 7.1 Discussion 7.2 Conclusions

8 References 9 Tables

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Document Name RH02061-201131 CSR Type Version Document Identifier Effective Date eldo_controlled 0.1; CURRENT; In Progress; Most-Recent 090032d580a5e8a0 Reason For Issue

T10.1_Disposition_v1 T14.1_Demography_v1 T14.2.1_Muscle_PCr_v1 T14.2.2_Change_Baseline_Muscle_PCr_v1 T14.2.3_ANCOVA_Primary_v1 T14.2.4.1_31PMRS_v1 T14.2.4.2_fMRI_v1 T14.2.5.1_Change_Baseline_31PMRS_v1 T14.2.5.2_Change_Baseline_fMRI_v1 T14.2.6.1_ANCOVA_Secondary_31P-MRS_v1 T14.2.6.2_ANCOVA_Secondary_fMRI_v1 T14.2.7.1_Secondary_Cognitive_v1 T14.2.7.2_Bond_Lader_v1 T14.2.8.1_Change_Baseline_Secondary_Cognitive_v1 T14.2.8.2_Change_Baseline_Bond_Lader_v1 T14.2.9.1_ANCOVA_Secondary_Cognitive_v1 T14.2.9.2_ANCOVA_Bond_Lader_v1 T14.2.10_Brain_PCr_v1.1 T14.2.11_Change_from_Baseline_Brain_PCr_v1.1 T14.2.12_ANCOVA_Exploratory_efficacy_v1.1 T14.3.1.1_Adverse_events_v1 T14.3.1.2_Drug_related_Adverse_events_v1 T14.3.3_Narratives_Adverse_events_v1

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GSK Medicine: CreatineStudy Number: 201131Title: A randomised, double-blind, study to investigate the effects of creatine supplementation on muscle energetics and cognitive function in young healthy male athletes and an ageing population using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and functional magnetic resonance imaging (fMRI)Rationale: The purpose of the study was to explore the effects of creatine supplementation on muscle Phosphocreatine(PCr) levels, muscle energetics and cognitive function in both healthy recreational athletes and healthy ageing population.The study also aimed to contribute to the GlaxoSmithKline (GSK) safety database for utilization of creatine monohydrate.Phase: IStudy Period: 17-Dec-2013 to 24-Jun-2014Study Design: This was a randomized, parallel group, double blind study in healthy male recreational athletes and healthy older male or female participants to study the effect of creatine supplementation on muscle energetic and cognitive function, using 31P-MRS and fMRI. Participants received either creatine supplemented protein drink (30 g whey protein and 5 g creatine powder) or control product (30 g whey protein and 5 g bulking agent powder). Initially, 9 participants in each group received creatine intervention and 3 received control. After an interim analysis, 1 further participant in each group received creatine intervention and a further 2 received control. Participants took products for 14 days, twice daily and complied with structural exercise intervention programme. They were assigned to study treatment in accordance with the randomisation schedule which was generated by the Hammersmith Medicines Research (HMR) statistician using a validated SAS® programme. All participants were evaluated for changes in muscle PCr levels and muscle energetics at days 0, 3, 7 and 14. They also underwent fMRI of the brain, 31P-MRS and cognitive function test at Day 0 and 14. During each Magnetic Resonance Imaging (MRI) scan, pulse oximetry data [including oxygen saturation (SpO2), pulse and heart rate] were monitored through finger clip.Centres: 1 sites, UKIndication: Nutritional StatusTreatment:

1. Creatine Intervention: Whey protein (30 g) and creatine powder (5 g)2. Control (Placebo): Whey protein (30 g) and bulking agent powder (5 g)

One serving included 1 sachet. Two daily servings (where 1 serving was 1 sachet mixed with 250-300 mL cold water) wastaken by the participants for 14 days. The first serving was taken with breakfast and the second within 60 min after completing training, or in the evening on non-training days.Objectives: To determine the effect of 14 days creatine supplementation on muscle PCr levels within 2 populations: healthy male recreational athletes and an ageing healthy populationPrimary Efficacy Variable: 31P-MRS measure of muscle PCr concentration at rest. The primary efficacy variable was measured by 31P-MRS (calf) as change in muscle PCr concentration at rest from baseline (Day 0) on Days 3, 7 and 14.Secondary Efficacy Variable:

(i) Change in PCr from end exercise to recovery(ii) PCr recovery rate (PCr (T1/2))(iii) Adenosine diphosphate (ADP) recovery rate (ADP (T1/2))(iv) Lowest pH measured during pedal test or recovery (Minimum pH)(v) Change in ADP from end exercise to recovery (IU)(vi) Pre-exercise pH(vii) Blood Oxygen Level Dependent (BOLD) signal in the brain(viii) Cognitive function

Change in PCr from end exercise to recovery, PCr T1/2, ADP T1/2 , minimum pH, change in ADP from end exercise to recovery (IU) and pre-exercise pH were measured as change from baseline (Day 0) on Days 3, 7 and 14 as measured by 31P-MRS on the leg. While, the change in BOLD signal in brain was measured by fMRI scan and cognitive working memory task of brain from baseline (Day 0) on Day 14. Changes in cognitive function were measured from baseline (Day 0) on Day 14 using standard battery assessment by CogState and Bond-Lader visual analogue scales (VAS).Statistical Methods: All participants who were randomized and received at least on dose of the trial supplement were included in safety population. The intent-to-treat (ITT) population comprised of all participants who received at least one dose of trial supplement and have at least one post-baseline efficacy assessment. The Per Protocol (PP) population was defined as all participants who complied with all trial procedures and restrictions, as described in the protocol and Statistical Analysis Plan. For the primary endpoints, the hypothesis tested were:Null Hypothesis: There was no difference between creatine supplementation and control [Difference (Diff) = 0] andAlternative Hypothesis: There was a difference between creatine supplementation and control (Diff ≠ 0)


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Where Diff was the estimate of the difference (creatine group minus control group) in the mean change from baseline, obtained from the Analysis of covariance (ANCOVA) model. Where the dependent variable was the change at Days 3, 7 and 14 and the factors were: trial supplement; age group; day; trial supplement by age; trial supplement by day; and supplement by group by day; and the covariates were baseline and baseline by day.Significance tests and confidence intervals (CI) were two sided, with alpha of 0.05. Point estimates, 95 % confidence intervals and p-values for the difference between trial supplements within age groups were produced from the ANCOVAand presented.Study Population: Healthy volunteers aged 18-35 years (male) and 50-70 years (male or female) with a body mass index in the range 19.0-29.9 and minimum dietary protein intake at or near 0.75 to 0.85 g protein/kg/day (recommended daily amount) were included. The participants who were included in 18-35 year age group were also participating in regular physical activity, 2-3 times a week for at least 6 months before study start.Participants with any of the following were excluded from the trial: Female volunteers of 18-35 years or pre-menopausal woman of 50-70 years. Any abnormal physical finding, acute or chronic illness or history of chronic illness that interfered with the trial objectives or participants safety. Presence or history of severe adverse reaction to any food, drug or sensitivity to nutritional supplements. Use of creatine or dietary or herbal supplement within 60 days before first administration of investigational product that claimed to increase muscle mass or metabolic rate or fat burning. Positive forhepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV)1 or HIV2, evidence of drug abuse, smoker or former smoker (past 6 months), presence or history of drug or alcohol abuse or intake of > 21 units alcohol weekly for men or 14 units of alcohol weekly for women. Loss of more than 400 mL blood during 3 months before trial start. Any impairment affecting mobility and muscle metabolism of lower limb, surgery or medical condition affecting supplement absorption. Metal implants that could interfere with MRI scan, history of claustrophobia or participant unable to lie for 90 min in MRI scanner or unable to perform required muscle exercise in MRI scanner. Use of steroids, anti-coagulant or oestrogen within 90 days before first administration of investigational product. Volunteers who took part in a clinical trial of new entity (past 3 months) or prescribed medicine within 30 days before first serving of study product or over-the-counter medicine (except paracetamol) during 7 days before study start. Change in body weight of > 5 Kg during 90 days before screening. Blood pressure outside the ranges 90–140 mm Hg systolic, 40–90 mm Hg diastolic, heart rate outside 35-100 beats/min (18-35 years; male) or 40-100 beats/min (50-70 years; male or female). Employees of sponsor or study sites or members of their immediate family were also excluded from the trial.Subject Disposition:Number of Subjects: Young Athletes Ageing Healthy

Control Creatine Intervention Control CreatineIntervention

Randomised, N 5 10 5 10Completed, n (% 5 10 5 10DemographicsN (Safety) 5 10 5 10Females: Male 0: 5 (100.0) 0: 10 (100.0) 4 (80.0):1 (20.0) 2 (20.0): 8 (80.0)

Mean Age, years (SD) 27.0 (4.85) 26.6 (4.99) 63.0 (6.32) 57.5 (4.30)Race, n (%) Asian 1 (20.0) 3 (30.0) 0 0 Black Or African American 2 (40.0) 1 (10.0) 0 1 (10.0) Mixed Middle-Eastern/Filipino 0 1 (10.0) 0 0 Mixed White/Hawaiian/Japanese 0 1 (10.0) 0 0 Mixed 1 (20.0) 0 0 0 White 1 (20.0) 4 (40.0) 5 (100.0) 9 (90.0)


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Primary Efficacy Results:Table 1. 31P-MRS measure of muscle PCr concentration at rest

Least Squares (LS) Means

Muscle PCr concentration at rest [Institutional

Units (IU)]

Age Group

PlannedRelative

Time

CreatineIntervention

(N=10)

Control(N=5)

Difference* 95%Confidence

Interval

p-value

Young Athletes

Day 3 0.92 0.91 0.02 (-0.07, 0.10) 0.68Day 7 1.01 0.91 0.10 ( 0.01, 0.18) 0.029

Day 14 1.01 0.91 0.10 ( 0.01, 0.18) 0.024

Ageing Healthy

Day 3 0.95 0.89 0.06 (-0.03, 0.15) 0.17Day 7 0.99 0.86 0.13 ( 0.05, 0.22) 0.0033

Day 14 1.07 0.85 0.21 ( 0.13, 0.30)

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Table 5. Lowest pH measured during pedal test or recovery (Minimum pH)LS Means

Minimum pH

Age Group PlannedRelative Time

Creatine Intervention

(N=10)

Control(N=5)

Difference* 95% Confidence

Interval

Young AthletesDay 3 6.68 6.78 -0.10 (-0.27, 0.08)Day 7 6.67 6.78 -0.12 (-0.29, 0.05)Day 14 6.71 6.77 -0.06 (-0.23, 0.11)

Ageing HealthyDay 3 6.87 6.76 0.11 (-0.06, 0.28)Day 7 6.79 6.78 0.01 (-0.16, 0.18)Day 14 6.72 6.75 -0.03 (-0.20, 0.14)

*Difference = Creatine Intervention - ControlTable 6. Change in ADP from end exercise to recovery (IU)

LS Means

Change in ADP from end exercise to recovery (IU)



(N=10)

Control(N=5)


Interval

Young AthletesDay 3 8.39 8.09 0.30 (-2.37, 2.96)Day 7 8.72 9.43 -0.71 (-3.37, 1.95)Day 14 9.95 8.38 1.57 (-1.09, 4.23)

Ageing HealthyDay 3 8.45 8.80 -0.36 (-2.89, 2.18)Day 7 8.09 6.60 1.49 (-1.01, 3.99)Day 14 8.54 8.72 -0.18 (-2.68, 2.32)

*Difference = Creatine Intervention - ControlTable 7. Pre-exercise pH

LS Means

Pre-exercise pH



(N=10)

Control(N=5)


Interval

Young AthletesDay 3 7.067 7.075 -0.008 (-0.035, 0.019)Day 7 7.068 7.067 0.002 (-0.025, 0.029)

Day 14 7.060 7.052 0.008 (-0.019, 0.035)

Ageing HealthyDay 3 7.061 7.046 0.015 (-0.013, 0.043)Day 7 7.062 7.059 0.003 (-0.024, 0.030)

Day 14 7.067 7.048 0.018 (-0.009, 0.045)*Difference = Creatine Intervention - ControlTable 8. BOLD signal in brain

LS Means

ParameterAge

GroupPlannedRelativeTime


(N=10)

Control(N=5)


Interval

fMRI Battery Task: Visual (% Signal Change)- Primary Visual

Cortex

Young Athletes

Day 14 3.38 4.34 -0.96 (-4.13, 2.22)

Ageing Healthy

Day 14 4.04 5.21 -1.17 (-4.05, 1.71)

fMRI Battery Task: Visual (% Signal Change)- Primary Auditory

Cortex

Young Athletes

Day 14 -6.80 -7.85 1.06 (-2.89, 5.01)

Ageing Healthy

Day 14 -5.80 -8.59 2.80 (-1.20, 6.80)

fMRI Battery Task: Visual (% Signal Change)-

Left Hemisphere (LH ) Linguistic regions

Young Athletes

Day 14 -0.24 -0.38 0.13 (-2.02, 2.29)

Ageing Healthy

Day 14 -0.36 -0.60 0.24 (-1.84, 2.32)


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Table 8. BOLD signal in brain (continued)LS Means

ParameterAge

GroupPlannedRelative

Time


(N=10)

Control(N=5)


Interval

fMRI Battery Task: Visual (% Signal Change)- Parietal Number

regions

Young Athletes

Day 14 0.42 1.21 -0.79 (-2.98, 1.39)

Ageing Healthy

Day 14 0.99 0.41 0.58 (-1.37, 2.54)

fMRI Battery Task: Visual (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 -0.21 0.22 -0.43 (-2.65, 1.78)

Ageing Healthy

Day 14 0.98 0.34 0.64 (-1.65, 2.93)

fMRI Battery Task: Auditory (% Signal Change)- Primary Visual

Cortex

Young Athletes

Day 14 -3.38 -4.34 0.96 (-2.22, 4.13)

Ageing Healthy

Day 14 -4.04 -5.21 1.17 (-1.71, 4.05)

fMRI Battery Task: Auditory (% Signal Change)- Primary Auditory

Cortex

Young Athletes

Day 14 6.80 7.85 -1.06 (-5.01, 2.89)

Ageing Healthy

Day 14 5.80 8.59 -2.80 (-6.80, 1.20)

fMRI Battery Task: Auditory (% Signal Change)- LH Linguistic

regions

Young Athletes

Day 14 0.24 0.38 -0.13 (-2.29, 2.02)

Ageing Healthy

Day 14 0.36 0.60 -0.24 (-2.32, 1.84)

fMRI Battery Task: Auditory (% Signal Change)- Parietal Number

regions

Young Athletes

Day 14 -0.42 -1.21 0.79 (-1.39, 2.98)

Ageing Healthy

Day 14 -0.99 -0.41 -0.58 (-2.54, 1.37)

fMRI Battery Task: Auditory (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 0.21 -0.22 0.43 (-1.78, 2.65)

Ageing Healthy

Day 14 -0.98 -0.34 -0.64 (-2.93, 1.65)

fMRI Battery Task: Linguistic (% Signal Change)- Primary Visual

Cortex

Young Athletes

Day 14 -1.36 -1.20 -0.17 (-1.44, 1.11)

Ageing Healthy

Day 14 -1.12 -1.52 0.40 (-0.69, 1.49)

fMRI Battery Task: Linguistic (% Signal Change)- Primary Auditory

Cortex

Young Athletes

Day 14 -0.00 0.09 -0.09 (-1.02, 0.83)

Ageing Healthy

Day 14 -0.04 0.34 -0.37 (-1.29, 0.54)


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ParameterAge


Creatine Intervention(N=10)

Control(N=5)


Interval

fMRI Battery Task: Linguistic (% Signal Change)- LH Linguistic

regions

Young Athletes

Day 14 0.18 0.10 0.08 (-0.63, 0.80)

Ageing Healthy

Day 14 0.55 0.48 0.06 (-0.61, 0.74)

fMRI Battery Task: Linguistic (% Signal Change)- Parietal Number

regions

Young Athletes

Day 14 -0.13 -0.08 -0.05 (-0.72, 0.62)

Ageing Healthy

Day 14 0.17 0.26 -0.09 (-0.73, 0.55)

fMRI Battery Task: Linguistic (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 -0.01 -0.22 0.21 (-0.40, 0.83)

Ageing Healthy

Day 14 -0.05 0.30 -0.35 (-0.94, 0.25)

fMRI Battery Task: Calculation (% Signal Change)- Primary Visual

Cortex

Young Athletes

Day 14 0.36 0.10 0.26 (-0.49, 1.00)

Ageing Healthy

Day 14 0.24 0.23 0.02 (-0.73, 0.76)

fMRI Battery Task: Calculation (% Signal Change)- Primary Auditory

Cortex

Young Athletes

Day 14 -0.02 -0.96 0.94 (0.21, 1.66)

Ageing Healthy

Day 14 -0.11 -0.76 0.65 (-0.08, 1.37)

fMRI Battery Task: Calculation (% Signal Change)- LH Linguistic

regions

Young Athletes

Day 14 0.21 0.18 0.03 (-0.57, 0.62)

Ageing Healthy

Day 14 0.32 0.25 0.07 (-0.53, 0.67)

fMRI Battery Task: Calculation (% Signal Change)- Parietal Number

regions

Young Athletes

Day 14 1.40 1.20 0.19 (-0.72, 1.11)

Ageing Healthy

Day 14 1.15 1.14 0.01 (-0.84, 0.87)

fMRI Battery Task: Calculation (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 0.43 0.14 0.29 (-0.41, 1.00)

Ageing Healthy

Day 14 0.14 -0.28 0.42 (-0.26, 1.11)

fMRI Battery Task: Motor (% Signal Change)- Primary Visual Cortex

Young Athletes

Day 14 -1.15 -2.60 1.45 (-0.53, 3.42)

Ageing Healthy

Day 14 -1.84 -2.66 0.82 (-1.12, 2.76)

fMRI Battery Task: Motor (% Signal Change)- Primary Auditory Cortex

Young Athletes

Day 14 1.45 -0.04 1.50 (-0.68, 3.68)

Ageing Healthy

Day 14 0.64 2.03 -1.39 (-3.61, 0.82)

fMRI Battery Task: Motor (% Signal Change)- LH Linguistic regions

Young Athletes

Day 14 0.64 -0.59 1.23 (-0.55, 3.02)

Ageing Healthy

Day 14 0.88 1.10 -0.22 (-2.00, 1.56)

fMRI Battery Task: Motor (% Signal Change)- Parietal Number regions

Young Athletes

Day 14 1.90 -0.01 1.90 (-0.26, 4.06)

Ageing Healthy

Day 14 1.70 2.28 -0.58 (-2.66, 1.51)


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ParameterAge



Control(N=5)


Interval

fMRI Battery Task: Motor (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 4.60 3.93 0.67 (-2.19, 3.53)

Ageing Healthy

Day 14 4.74 4.80 -0.07 (-2.93, 2.80)

0-Back (% Signal Change): Middle Frontal

Young Athletes

Day 14 0.35 0.37 -0.02 (-0.32, 0.27)

Ageing Healthy

Day 14 0.23 0.36 -0.14 (-0.42, 0.15)

0-Back (% Signal Change): Pallidum/Striatum

Young Athletes

Day 14 0.21 0.02 0.19 (-0.12, 0.50)

Ageing Healthy

Day 14 -0.07 0.21 -0.27 (-0.57, 0.02)

0-Back (% Signal Change): ParietalYoung

AthletesDay 14 0.31 0.27 0.04 (-0.30, 0.39)

Ageing Healthy

Day 14 0.04 0.29 -0.25 (-0.59, 0.09)

0-Back (% Signal Change): Superior Frontal

Young Athletes

Day 14 0.08 0.18 -0.10 (-0.39, 0.19)

Ageing Healthy

Day 14 0.00 0.24 -0.24 (-0.50, 0.03)

0-Back (% Signal Change): Supplementary Motor Area

Young Athletes

Day 14 0.21 0.30 -0.09 (-0.48, 0.31)

Ageing Healthy

Day 14 0.08 0.29 -0.22 (-0.55, 0.12)

2-Back (% Signal Change): Middle Frontal

Young Athletes

Day 14 0.72 0.64 0.08 (-0.24, 0.41)

Ageing Healthy

Day 14 0.68 0.77 -0.10 (-0.42, 0.23)

2-Back (% Signal Change): Pallidum/Striatum

Young Athletes

Day 14 0.43 0.13 0.30 (-0.01, 0.60)

Ageing Healthy

Day 14 0.12 0.35 -0.23 (-0.53, 0.07)

2-Back (% Signal Change): ParietalYoung

AthletesDay 14 0.81 0.63 0.19 (-0.22, 0.59)

Ageing Healthy

Day 14 0.67 0.87 -0.20 (-0.58, 0.18)

2-Back (% Signal Change): Superior Frontal

Young Athletes

Day 14 0.49 0.42 0.07 (-0.15, 0.29)

Ageing Healthy

Day 14 0.41 0.62 -0.22 (-0.43, -0.00)

2-Back: Supplementary Motor AreaYoung

AthletesDay 14 0.49 0.49 0.00 (-0.28, 0.28)

Ageing Healthy

Day 14 0.42 0.65 -0.22 (-0.49, 0.05)

Motor Task (% Signal Change): Simple- Intra-parietal Sulcus

Young Athletes

Day 14 -0.19 0.08 -0.27 (-0.59, 0.05)

Ageing Healthy

Day 14 -0.01 0.04 -0.05 (-0.37, 0.27)


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ParameterAge



Control(N=5)


Interval

Motor Task: Simple (% Signal Change)- Pre-Motor Cortex

Young Athletes

Day 14 0.19 0.09 0.10 (-0.27, 0.47)

Ageing Healthy

Day 14 0.28 0.29 -0.01 (-0.38, 0.37)

Motor Task: Simple (% Signal Change)- Supplementary Motor

Area

Young Athletes

Day 14 0.40 0.09 0.31 (-0.21, 0.82)

Ageing Healthy

Day 14 0.30 0.43 -0.13 (-0.63, 0.37)

Motor Task: Simple (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 0.42 0.41 0.01 (-0.37, 0.39)

Ageing Healthy

Day 14 0.37 0.47 -0.10 (-0.47, 0.28)

Motor Task: Complex (% Signal Change)- Intra-parietal Sulcus

Young Athletes

Day 14 0.59 0.46 0.13 (-0.28, 0.54)

Ageing Healthy

Day 14 0.55 0.78 -0.24 (-0.64, 0.17)

Motor Task: Complex (% Signal Change)- Pre-Motor Cortex

Young Athletes

Day 14 0.92 0.67 0.25 (-0.20, 0.69)

Ageing Healthy

Day 14 0.89 0.95 -0.06 (-0.50, 0.38)

Motor Task: Complex (% Signal Change)- Supplementary Motor

Area

Young Athletes

Day 14 0.98 0.42 0.56 (0.01, 1.10)

Ageing Healthy

Day 14 0.65 0.73 -0.08 (-0.62, 0.47)

Motor Task: Complex (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 1.04 0.98 0.06 (-0.40, 0.52)

Ageing Healthy

Day 14 0.87 1.00 -0.12 (-0.58, 0.33)

Motor Task: Self-Selected (% Signal Change)- Intra-parietal

Sulcus

Young Athletes

Day 14 0.08 0.25 -0.17 (-0.57, 0.23)

Ageing Healthy

Day 14 0.06 0.12 -0.06 (-0.45, 0.34)

Motor Task: Self-selected (% Signal Change)- Pre-Motor Cortex

Young Athletes

Day 14 0.31 0.23 0.08 (-0.29, 0.45)

Ageing Healthy

Day 14 0.20 0.29 -0.09 (-0.46, 0.27)

Motor Task: Self-selected (% Signal Change)- Supplementary

Motor Area

Young Athletes

Day 14 0.57 0.22 0.35 (-0.14, 0.84)

Ageing Healthy

Day 14 0.24 0.42 -0.19 (-0.68, 0.31)

Motor Task: Self-selected (% Signal Change)- LH Motor Cortex

Young Athletes

Day 14 0.72 0.61 0.11 (-0.34, 0.55)

Ageing Healthy

Day 14 0.40 0.49 -0.09 (-0.53, 0.36)

* Difference = Creatine Intervention - Control


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Table 9. Cognitive function by Cogstate battery and Bond-Lader VASLS Means

ParameterAge Group Planned

RelativeTime


(N=10)

Control(N=5)


Interval

Detection [log10 milisecond (msec)]

Young Athletes

Day 14 2.45 2.41 0.04 (-0.03, 0.11)

Ageing Healthy

Day 14 2.46 2.42 0.04 (-0.03, 0.11)

Identification (log10 msec)Young

AthletesDay 14 2.63 2.61 0.02 (-0.02, 0.06)

Ageing Healthy

Day 14 2.65 2.62 0.04 (0.00, 0.08)

One-card learning (arcsine square root proportion correct)

YoungAthletes

Day 14 1.11 1.08 0.03 (-0.10, 0.15)

Ageing Healthy

Day 14 1.03 1.11 -0.08 (-0.20, 0.04)

One-back memory (log10 msec)

Young Athletes

Day 14 2.80 2.80 -0.00 (-0.09, 0.08)

Ageing Healthy

Day 14 2.83 2.77 0.05 (-0.03, 0.14)

Groton maze learning test (total errors)

Young Athletes

Day 14 33.82 38.80 -4.98 (-17.30, 7.35)

Ageing Healthy

Day 14 44.53 57.70 -13.17 (-25.93, -0.40)

Continuous paired associate learning (total errors)

Young Athletes

Day 14 36.08 33.02 3.07 (-51.83, 57.97)

Ageing Healthy

Day 14 85.20 57.01 28.19 (-26.88, 83.26)

Alertness (mm) (as measured from Bond-Lader VAS)

Young Athletes

Day 14 433.18 419.98 13.20 (-15.09, 41.49)

Ageing Healthy

Day 14 417.29 408.87 8.42 (-19.48, 36.31)

Contentedness (mm) (as measured from Bond-Lader

VAS)

Young Athletes

Day 14 254.20 267.39 -13.19 (-35.11, 8.74)

Ageing Healthy

Day 14 264.22 257.77 6.45 (-15.95, 28.84)

Calmness (mm) (as measured from Bond-Lader VAS)

Young Athletes

Day 14 105.37 109.32 -3.95 (-31.21, 23.31)

Ageing Healthy

Day 14 104.52 108.71 -4.19 (-31.51, 23.12)

* Difference = Creatine Intervention - ControlSafety Results: Adverse events (AEs) were collected from the start of treatment until 5 days after the last administration of the investigational product. Serious adverse events (SAEs) were collected over the same time period.


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Table 10. Summary of Treatment-Emergent Adverse Events

Young Athletes Ageing HealthySystem Organ Class Control

(N=5)Creatine

Intervention(N=10)

Control(N=5)


(N=10)Number of subjects with AEs, n (%) 2 (40.0) 3 (30.0) 0 5 (50.0)Nervous system disorders

Headache 0 1 (10.0) # 0 3 (30.0)**Injury, poisoning and procedural complications

Arthropod bite 0 1 (10.0) 0 0 Laceration 1 (20.0) 0 0 0

Gastrointestinal disorders Abdominal pain 0 0 0 1 (10.0) Constipation 0 0 0 1 (10.0)

Immune system disordersSeasonal allergy 0 1 (10.0) 0 0

Infections and infestationsUpper respiratory tract infection 1 (20.0) 0 0 0

Respiratory, thoracic and mediastinal disordersRhinorrhoea 0 0 0 1 (10.0)

Skin and subcutaneous tissue disordersRash pruritic 0 1 (10.0) # 0 0

# Drug-related treatment-emergent adverse event** One out of three participants experienced headache as drug-related treatment-emergent AESerious Adverse Events - On-Therapy n (%): There were no deaths, no fatal and/or non-fatal serious adverse events.


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List of Abbreviations

31P-MRS Phosphorus-31 magnetic resonance spectroscopy

ADP Adenosine diphosphate

AE Adverse event

ANCOVA Analysis of covariance

ATP Adenosine triphosphate

BMI Body mass index

BOLD Blood oxygen level dependent

CRF Case report form

ECG Electrocardiography

fMRI Functional magnetic resonance imaging

GCP Guideline for Good Clinical Practice

GSK GlaxoSmithKline

h Hour

HMR Hammersmith Medicines Research

ICH International Conference on Harmonisation

IU Institutional Units

LBM Lean body mass

MedDRA Medical Dictionary for Regulatory Activities

MRI Magnetic resonance imaging

PCr Phosphocreatine

REC Research ethics committee

SAE Serious adverse event

SAP Statistical Analysis Plan

TFL Tables, figures and listings

T½ Recovery half-time

TEAE Treatment-emergent adverse event

VAS Visual analogue scale


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Ethics

Independent Ethics Committee or Institutional Review Board

The trial proposal was reviewed by

The trial was not started until written approval had been obtained from the

ethics committee.

The trial protocol is provided in Appendix 1.1, and approval from the ethics

committee is provided in Appendix 1.3.

Ethical Conduct of the Study

The trial was done at Hammersmith Medicines Research (HMR) and Imanova in

accordance with their standard operating procedures, and in compliance with the

World Medical Association Declaration of Helsinki (Seoul, 2008), International

Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), and

other applicable regulations.

All data generated during the trial are archived at HMR and will be stored for at least

15 years. The sponsor will be consulted before any trial documents are destroyed.

Subject Information and Consent

All subjects gave written consent to participate in this trial. Before giving consent,

subjects read the information about the trial. They then discussed the trial with the

investigator or his delegate and were given the opportunity to ask questions. The

trial-specific information sheet and the consent form were approved by the main

REC.

A sample informed consent form is provided in Appendix 1.3.


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Investigators and Study Administrative Structure

Chief Investigator: Frans van den Berg MBChBHMRCumberland AvenuePark RoyalLondon NW10 7EWTel: Fax:

Principal Investigator: Eugenii A Rabiner BSc MBBCH FCPsych (SA)Imanova Ltd.Burlington Danes BuildingImperial College London,Hammersmith HospitalDu Cane Road, London, W12 0NNtel: fax:

Co-investigators: Malcolm Boyce BSc FRCP FFPMAdeep Puri MPhil MBBSIngeborg Loewenstein MDDenisa Wilkes MBBS

HMR

Study Co-ordinator: BSc PhDHMR

Quality Assurance BScHMR

Analytical Laboratory: BSc FIBMSThe HMR Analytical LaboratoryHMR

Protocol Authors: BSc PhD BSc MSc CStat MBA

MBChBHMR

Report Authors: BSc PhD BSc MRes PhD

HMR

Study Monitor:Tel:

Statistician: BSc MSc CStat MBAHMR

Data Management: BScHMR


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1 Introduction

Creatine is a non-essential dietary compound that can be both endogenously

synthesised, primarily in the liver, and ingested through omnivorous diets, with the

greatest natural quantity of creatine present in red meats [Braun et al., 2011].

Creatine has become a popular supplement for athletes, with European food

regulators supporting a link between creatine consumption and ‘an increase in

physical performance during short-term, high intensity, repeated exercise bouts’.

About 90–95% of the body’s creatine is found in skeletal muscle. Of this, about

one-third is free creatine, whereas two-thirds exist as phosphocreatine (PCr). It has

repeatedly been shown that the muscle concentration of total creatine can be

increased by oral creatine supplementation.

The aim of creatine supplementation is to increase the intracellular pool of total

creatine (creatine + PCr). The intracellular concentration of PCr plays a significant

role in the immediate bioenergetic system, which is most active during exercise at

high intensity and short duration, and during repeated bouts of physical activity. In

the first few seconds of sprinting or high intensity exercise, creatine phosphate is the

most important fuel source. Consequently, creatine supplementation regimes that

maximise muscle creatine levels can lead to improved performance in repeated high

intensity exercise, increased strength and lean body mass (LBM), and enhanced

fatigue resistance in exercise activities lasting 30 seconds or less. Thus, creatine is

relevant in many training programmes including resistance exercise, sprint training

and team sports involving intermittent work patterns including high bursts of activity.

While creatine supplementation has now become commonplace for athletes, there

may be benefits for other populations as well. In particular, there may be benefits in

the ageing population as a way to maintain muscle function and activity. Less is

known about the potential benefits of creatine in the ageing population than in

athletes.

Creatine supplementation has also been demonstrated to improve measures of

cognitive function, such as memory, in various populations (vegetarians, athletes and

sleep-deprived individuals) over varying time frames [Hammett et al., 2010]. The

exact mechanism by which creatine can improve cognitive performance is not fully

understood, but it may be related to blood-brain flow or to cerebral metabolism.

Although creatine supplementation has been widely used by athletes to improve

performance in training, the purpose of this study was to explore the impact of

creatine supplementation on muscle energetics in both athletes and an ageing


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population. The study also evaluated the effect of creatine supplements on cognitive

functions.

2 Study Objectives

2.1 Primary Objective

To determine the effect of 14 days’ creatine supplementation on muscle

PCr levels within 2 populations: healthy male recreational athletes and an

ageing healthy population.

2.2 Secondary Objectives

To explore the impact of 14 days’ creatine supplementation on muscle

energetics within 2 populations: healthy recreational athletes and an


To determine the effect of 14 days’ creatine supplementation on cognitive

function within 2 populations: healthy male recreational athletes and an


To assess the safety and tolerability of 14 days’ creatine supplementation.

2.3 Exploratory Objective

To explore the impact of 14 days’ creatine supplementation on brain PCr

levels within 2 populations: healthy male recreational athletes and an


3 Investigational Plan

3.1 Overall Study Design and Plan Description

This was a randomised, double-blind study of the effects of creatine supplementation

on muscle energetics and cognitive function, using phosphorus-31 magnetic

resonance spectroscopy (31P-MRS) and functional magnetic resonance imaging

(fMRI).

15 healthy male recreational athletes (Group 1) and 15 healthy older subjects

(Group 2) were enrolled. In each group, 10 subjects took a creatine supplemented

protein drink (combined whey protein and creatine: 5 g creatine, 30 g whey protein),

and 5 took a control product (whey protein only and placebo powders: 30 g whey


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protein). Subjects took the products twice daily for 14 days, at home, and complied

with a structured exercise intervention programme.

3.1.1 Study visits

Subjects were screened (at HMR) within 28 days of taking their first supplement.

They returned to HMR for outpatient visits on Days 0, 3, 7 and 14 (Visits 1, 2, 3 and

4). They also returned to HMR for exercise sessions 3 times each week.

3.1.2 Study assessments

The following assessments were made.

Efficacy: muscle energetics and brain function assessments.

31P-MRS measurement of leg muscle and brain creatine, fMRI of brain, and

cognitive function tests, as shown in the following table.

Day Visit

Assessments31P-MRS of leg

muscle

31P-MRS of

brain

fMRI of brain Cognitive

function

0 1 X X X X

3 2 X

7 3 X

14 4 X X X X31P-MRS: phosphorus-31 magnetic resonance spectroscopy; fMRI: functional magnetic resonance imaging.

Leg muscle PCr concentrations were calculated during exercise and in the

post-exercise metabolic recovery phase. Brain PCr concentrations were also

calculated.

Changes in the blood oxygen level dependent (BOLD) signal during a series of

cognitive tests, and at rest, were recorded. Structural MRI scans were used to localise

brain regions. Cognitive function tests were done using the CogState standard battery

of tests for GlaxoSmithKline (GSK) Consumer Healthcare nutrition intervention

studies.

Safety and tolerability: vital signs and adverse events (AEs). Pulse oximetry

(including oxygen saturation, pulse and heart rate) was monitored during MRI scans.


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3.2 Discussion of Study Design, including the Choice of Control Groups

The double-blind design of the trial had the important advantage that neither the

investigator nor subjects were aware of who was receiving active treatment. The

possibility of bias was therefore reduced, particularly in the assessment of AEs; most

of the other assessments in the present trial were objective, either because they were

measured by laboratory staff, or using automated devices eg heart rate, blood pressure

and MRI scanners.

To meet the objectives of the trial, subjects took the maximum recommended daily

dose of each supplement for 14 days, in combination with a structured exercise

programme.

Efficacy, safety and tolerability assessments were done, as detailed in Section 3.1.2.

This study provided supporting data for a claims dossier on the benefits of creatine in

muscle energetics and cognitive function in two key demographics: 1) young,

healthy recreational athletes and 2) older individuals. The study also contributed to

the GSK safety database for utilisation of creatine monohydrate.

3.3 Selection of Study Population

30 subjects (15 recreational athletes and 15 healthy older subjects) were enrolled in

the study.

3.3.1 Inclusion criteria

Subjects were eligible for inclusion in the trial if they met the following criteria.

1. Healthy volunteer: Group 1: male; Group 2: male or female.

2. Aged 18–35 years (Group 1) or 50–70 years (Group 2).

3. A body mass index (BMI; Quetelet index) in the range 19.0–29.9 kg/m2.

4. Ability to understand the nature of the study and any hazards of participating in

it. Ability to communicate satisfactorily with the investigator and to participate

in, and comply with the requirements of, the entire study.


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5. Willingness to give written consent to participate after reading the information

and consent form, and after having the opportunity to discuss the study with the

investigator or his delegate.

6. Minimum dietary protein intake at or near the current recommended daily

amount (0.75 to 0.85 g protein/kg/day).

7. Participation in regular physical activity (aerobic and resistance training)

2–3 times a week for at least 6 months before the study starts (Group 1 only).

8. Willingness to maintain a stable lifestyle throughout the study.

9. Willingness to give written consent to have data entered into The

Overvolunteering Prevention System (to verify no recent participation in a

clinical trial of an investigational medicinal product).

3.3.2 Exclusion criteria

Subjects were excluded from the trial if they met the following criteria.

1. Female (Group 1), or pre-menopausal woman (Group 2).

2. Clinically relevant abnormal history, physical findings, electrocardiogram (ECG)

or laboratory values at the pre-trial screening assessment that could have

interfered with the objectives of the trial or the safety of the volunteer.

3. Presence of acute or chronic illness or history of chronic illness sufficient to

invalidate the volunteer’s participation in the trial or make it unnecessarily

hazardous.

4. Impaired endocrine, thyroid, hepatic, respiratory, neurological or renal function,

diabetes mellitus, cardiovascular disease, coagulation disorder, autoimmune

disease, phenylketonuria, hyperlipidaemia or history of any psychotic mental

illness.

5. Any impairment affecting mobility and muscle metabolism of the lower limbs

(such as arthritis).

6. Surgery (eg stomach bypass) or medical condition that might affect absorption of

supplements.


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7. Presence or history of severe adverse reaction to any drug or food, or a history of

sensitivity to nutritional supplements.

8. Use of creatine supplements, or any other dietary or herbal supplement claimed

to increase muscle mass or to increase metabolic rate or ‘fat burning’, within the

60 days before the first serving of investigational product.

9. Use of steroids, anti-coagulants or oestrogen (including hormone replacement

therapy) within the 90 days before the first serving of investigational product.

10. Use of any other prescription medicine during the 30 days before the first serving

of investigational product or over-the-counter medicine (except for paracetamol),

during the 7 days before the first serving of investigational product.

11. Participation in a clinical trial of a new chemical entity or prescribed medication

within 3 months of the first serving of investigational product.

12. Presence or history of drug or alcohol abuse, or intake of more than 21 units of

alcohol weekly (for men) or 14 units of alcohol weekly (for women).

13. Smoker or former smoker in the past 6 months.

14. Change in body weight of more than 5 kg during the 90 days before screening.

15. Inability to complete the structured exercise programme.

16. Blood pressure and heart rate in seated position at the screening examination

outside the ranges 90–140 mm Hg systolic, 40–90 mm Hg diastolic; heart rate

35–100 beats/min (Group 1) or 40–100 beats/min (Group 2).

17. Possibility that the volunteer would not cooperate with the requirements of the

protocol.

18. Evidence of drug abuse on urine testing.

19. Positive test for hepatitis B, hepatitis C or human immunodeficiency virus 1 or 2.

20. Loss of more than 400 mL blood during the 3 months before the trial, eg as a

blood donor.

21. Metal implants that may have affected the MRI scan, eg gold tooth or other metal

dental devices (normal dental fillings were allowed), pacemaker, mechanical


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heart valve, replacement joint, shrapnel. If any metal in the body was identified,

the investigators were to decide whether the subject should participate in the

study.

22. History of claustrophobia or subject felt unable to lie still on their back for a

period of 90 min in the MRI scanner, or subject was unable to perform the

required muscle exercise in the MRI scanner.

23. Employees of the sponsor or the study sites or members of their immediate

family.

3.3.3 Subject restrictions

3.3.3.1 Lifestyle

Subjects:

maintained a stable lifestyle and their normal dietary intake throughout the study

were encouraged to drink at least 2 L water daily during the treatment phase

fasted (no food or drink except water) from midnight before the muscle energetic

assessments at Visits 1–4 – after those assessments, subjects were given a

standardised breakfast

did not drink alcohol or consume anything containing caffeine for 24 h before

Visits 1–4

did a structured exercise programme during the study – they did no additional

strenuous exercise during the treatment phase or for 3 days before laboratory

safety tests at screening, and they did no exercise in the 24 h before Visits 1–4

3.3.3.2 Medications and treatments

Medication that was prohibited before the study (see Section 3.3.2) was also

prohibited during the study.

Any concomitant medication taken in the 30 days before the screening visit, or during

the study, was recorded.


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3.3.4 Removal of subjects from therapy or assessment

Criteria for withdrawal from the trial and exclusion from the statistical analysis were

described in the protocol (Appendix 1.1), as were the procedures to be followed if a

subject was withdrawn. In the event, no subject withdrew from the study.

3.4 Treatments

3.4.1 Treatments administered

In each group, 10 subjects took by mouth a creatine supplement drink and 5 subjects

took a matching placebo drink. Subjects took 2 daily servings for 14 days (Day 0 to

Day 13 inclusive): 1 with breakfast and another within 60 min after completing a

training session, or in the evening on non-training days.

Subjects took the first serving of study product at HMR at the end of Visit 1. They

took subsequent doses at home, except for servings on the mornings of Visits 1–4,

which they drank at HMR, after the imaging assessments.

3.4.2 Identity of investigational products

Packaging and labeling of all trial supplements was done according to ICH GCP

guidelines, and was managed by GSK Consumer Healthcare Clinical Supplies in

GSK House in the United Kingdom. Each serving of investigational product was

provided in a single sachet, as follows:

creatine supplement: 30 g whey protein powder and 5 g creatine powder

matching placebo supplement: 30 g whey protein powder and 5 g bulking agent

powder

The content of each sachet was dissolved in 250–300 mL cold water for oral

ingestion. Subjects were to drink all of the supplement, at each serving.

The batch number RH2061 was given to the supplements used in this study.

Supplement was stored at 25˚C or below – there was no expiry.

3.4.3 Treatment assignment

Subjects who met all the entry criteria were randomised according to the

randomisation schedule, and given a unique study-specific subject number. Subjects

in Group 1 were numbered ; subjects in Group 2 were numbered


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Within each group, subject numbers were assigned in ascending numerical

order in the order in which subjects were enrolled into the trial.

The randomisation schedule was prepared by HMR. Initially, 24 subjects were

enrolled in the study – 12 in each group: 9 subjects took the creatine supplement and

3 subjects took matching placebo. Following a protocol-specified review of

unblinded data by GSK staff not involved in study conduct, a further 3 subjects were

enrolled in each group: 1 subject took the creatine supplement and 2 took matching

placebo. HMR updated the randomisation schedule accordingly.

3.4.4 Selection of doses in the study

The selected dose was the maximum recommended daily amount of the supplement

marketed by GSK and used for enhancing muscular strength and mass.

3.4.5 Selection and timing of dose for each subject

Allocation to treatment/treatment group was done as described in Section 3.4.3.

Treatment administration is described in Section 3.4.1.

3.4.6 Blinding

This was a double-blind study. The supplements were supplied in identical sachets,

and were labelled for each subject. To maintain blinding, all shakers (blender bottles)

were also identical.

The study statistician, data management staff, and employees of the sponsor who may

have influenced study outcomes were blinded to the treatment allocation of subjects.

The unblinded data review was restricted to 3 GSK staff not involved in study

conduct: a statistician, imaging scientist and nutrition scientist.

The code was to be broken only in an emergency where it was essential to know

which treatment a subject received in order to give the appropriate medical care.

Wherever possible the investigator (or designee) was to contact the Sponsor before

breaking the code. The investigator was to document the reason for breaking the

code, and sign and date the appropriate document.

3.4.7 Treatment compliance

Subjects returned any unused sachets at each of visits 2 and 4. They used a diary card

to record product administration. Subjects with a product compliance rate of

13

were to be instructed to be more diligent about their dosing, and were to be allowed to

continue at the discretion of the investigator.

Deviations from the product administration procedure (ie compliance

14

Table 1: Schedule of trial procedures

Schedule Screening Visit 1 Baseline Visit 2 Interim Visit 3 Interim Visit 4 FinalDay -28 to -1 0 3 (+/-1) 7 (+/-1) 14 (+/-1)Informed consent1 XDemographics1 XMedical history1 XVital signs (blood pressure, pulse)1 X X X X XWeight and height1,11 X X X X XCalculate body mass index1 X12-Lead electrocardiogram1 XPhysical examination1 XUrine drug screen1 X X X X XFollicle-stimulating hormone test1 XLaboratory safety tests1,2 X XSerology tests1 XCarbon monoxide and alcohol breath test1 X X X X XPhysical activity history1 XMagnetic resonance imaging questionnaire1,6 X1 X X X XInclusion/exclusion criteria check1 X X X XRandomisation1 XStandard breakfast3 X X X XInvestigational product distribution1,4 X XDistribution/collection of diary cards1,5 X X X XStructured exercise programme10 X X31P-MRS of leg muscle6,7 X X X X31P-MRS of brain6 X XFunctional magnetic resonance imaging6 X XCognitive function test8 X1 X8 X8

Concomitant medication check1 X X X X XAssess and collect adverse events9 X X X X XRelease subject from study6 XData source: 13-012 trial protocol (version 8, dated 06 December 2013).

31P-MRS: phosphorus-31 magnetic resonance spectroscopy.

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1. Procedure was done at Hammersmith Medicines Research (HMR).2. Laboratory safety assessments included a routine chemistry and haematology profile. 3. Standard breakfast was provided by HMR, and consumed at Imanova after leg muscle kinetic assessments.4. Subjects collected investigational product sufficient for 7 days, twice daily home dosing.5. Diary cards were used to assess compliance with treatment and the exercise programme, and to collect adverse events and concomitant medication.6. Procedure was done at Imanova.7. Subjects were required to fast before muscle creatine/kinetic assessments.8. Cognitive function test training was carried out at screening at HMR, all subsequent cognitive function tests were at Imanova. On Day 0, subjects had

another cognitive function test training session, separated by at least 15 min, before they carried out the cognitive function tests.9. Adverse events were collected in diary cards; subjects were questioned about adverse events when they attended HMR.10. Subjects practised the exercises during the screening phase, to ensure that they were able to complete the programme. Subjects complied with the structured

exercise programme throughout the treatment phase. 11. Height was recorded at screening only.

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3.5.2 Screening methods, measurements and evaluations

3.5.2.1 Demographics and medical history

Each subject’s year of birth, sex and race was recorded. Medical history, including

medical or surgical history, allergies or drug sensitivity, was recorded and reviewed

by the investigator or medically qualified designee.

3.5.2.2 Physical examination and ECG

Examinations were done by a physician. The following were examined: general

appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back and neck;

heart; chest; lungs; abdomen; skin; and extremities; and the following systems were

assessed: musculoskeletal and neurological.

A standard 12-lead ECG was recorded at screening only. A 12-lead ECG was

recorded using a Mac 5000 (Marquette) cardiograph. The recording was printed on a

single A4 page at paper speed 25 mm/sec and calibrated to 1 cm/mV, or to

0.5 cm/mV if the amplitude of the QRS complex required that. Recordings were

made with subjects in a supine position; subjects remained supine for at least 10 min

before the ECG was recorded.

3.5.2.3 Physical activity history and assessment

Subjects were questioned about their exercise history to assess eligibility (Group 1

only) and to assess their ability to comply with the study exercise requirements. A

qualified personal trainer assessed each subject’s ability to complete the training

programme. The assessment included a load test to determine weights to be used

during the training sessions.

3.5.2.4 Laboratory safety tests

The HMR Analytical Laboratory ran safety tests on blood samples using analysers

interfaced to a validated laboratory information management system. Data from

analysers that were not interfaced were entered manually into this system.

The HMR Analytical Laboratory ran safety tests on blood and urine samples as

follows:

Haematology: haemoglobin, red blood cell count, mean cell volume, mean

corpuscular haemoglobin, mean corpuscular haemoglobin concentration,

haematocrit, white blood cell count and differential, and platelets;


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Biochemistry: urea, creatinine, uric acid, total bilirubin, total protein, albumin,

globulin, alkaline phosphatase, aspartate aminotransferase, alanine

aminotransferase, gamma glutamyl transpeptidase, glucose, phosphate,

cholesterol, triglycerides, potassium, sodium, calcium, and chloride;

Urinalysis: dipstick test: protein, blood, ketones, glucose, bilirubin,

urobilinogen, leukocyte esterase, specific gravity, nitrites, pH. Microscopy was

done on urine samples if the result of the dipstick test for protein, blood,

leukocyte esterase or nitrites was abnormal.

Follicle-stimulating hormone (to confirm post-menopausal status only).

The investigator could request additional safety tests if deemed necessary, for

example, coagulation or cystatin C tests.

Abnormal results that occurred during the defined time period for AE reporting and

that the investigator considered to be clinically significant were also to be recorded as

an AE or serious adverse event (SAE). If the clinically significant abnormal

laboratory result was associated with a diagnosis, the diagnosis was to be recorded.

Methods of analysis

Blood samples were taken by venepuncture for haematology (2 mL in

ethylenediamine tetra-acetic acid), and biochemistry and serology (2 × 2.5 mL in

tubes with a gelatin plug). Blood was collected into 13 × 75 mm tubes. Urine was

collected in 60 mL Universal containers. Samples were then transferred to the

laboratory.

Processing of blood samples was done by the HMR Analytical Laboratory. Blood

samples for biochemistry and serology were allowed to clot at room temperature for

20–90 min. After clotting, the tubes were centrifuged at about 1660 G for 6 min at

room temperature, and then stored at 4–25°C before analysis. Blood samples for

haematology were stored at 4–25°C before analysis. Biochemistry and haematology

analyses were usually done within 12 h after sample collection.

3.5.3 Efficacy measurements and evaluations

A summary of the efficacy assessments is provided below. Further details are

provided in the protocol (Appendix 1.1).


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3.5.3.1 Imaging assessments

31P-MRS of leg muscle

A 31P-MRS scan was acquired, and concentration of PCr in the leg muscle was

estimated during exercise and recovery, as detailed in the table below.

Phase Duration AssessmentRest Approximately 2 min Static magnetic resonance spectra were

acquired at rest up to 2 minExercise ≤20 min Subjects were instructed to plantarflex fully

against the weighted pedal periodically for up to 20 min or as tolerated. The weight of the pedal was 20% of the subjects’ LBM forthe young group, and 15% of LBM for the healthy elderly group. For these purposes,LBM was calculated from height and weight using the formula in Hume (1966).

Recovery ≤20 min Dynamic magnetic resonance spectra were acquired with the patient at rest for up to 20 min

LBM: lean body mass.

fMRI of brain

Subjects underwent an fMRI scan of the brain to estimate the BOLD signal during a

series of cognitive tests. In addition, subjects underwent a resting states network scan

and a structural MRI scan for localisation of brain regions.

31P-MRS of brain

A 31P-MRS scan was acquired, and concentration of PCr in the brain was estimated.

MRS data were recorded under 2 conditions. Firstly, a static scan at rest, with no

stimulation. Secondly, a dynamic scan with periodic visual stimulation. The visual

stimulus was a counter-phasing (8 Hz) black and white checkerboard with a

concentric arrangement, scaled in approximate accordance with the cortical

magnification factor, and it subtended approximately 20 degrees of visual angle. This

stimulus was presented for 3 seconds, followed by 27 seconds of a blank screen.

Subjects were instructed to maintain fixation on a small red fixation point that was

present throughout. The stimulus was repeated 12 times to give a total scan time of

6 min.


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3.5.3.2 Cognitive function assessments

The CogState-GSK nutrition battery was used to examine changes in behavioural

measures of cognition, including speed of processing (detection task),

attention/vigilance (identification task), working memory (one-back memory task),

visual learning and memory (one card learning task; continuous Paired Associate

Learning Task) and reasoning and problem solving (Groton Maze learning task). In

addition, Bond-Lader visual analogue scales (VAS) were used to assess subjective

mood state.

3.5.4 Structured exercise programme

During the treatment phase, subjects reported to HMR 3 times each week to complete

the structured training programme. Training sessions were done under supervision of

a qualified personal trainer, who documented subjects’ compliance with the

programme. Training sessions were tailored to the ability of each subject. Each

training session lasted about 40 min for Group 1; the duration of exercise for subjects

in Group 2 was tailored to the subject’s ability. Subjects carried out exercises

targeted at their leg muscles. Each session included interval cycling (alternating

periods of high and low activity), and calf raises and leg presses.

3.5.5 Safety measurements and evaluations

3.5.5.1 Adverse events

An AE was any untoward medical occurrence in a patient or clinical investigation

subject, temporally associated with the use of an investigational product, whether or

not considered related to the investigational product.

An AE could therefore have been any unfavourable and unintended sign (including an

abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally

associated with the use of an investigational product

Events meeting the definition of an AE included:

exacerbation of a chronic or intermittent pre-existing condition including either

an increase in frequency and/or intensity of the condition

new condition(s) detected or diagnosed after investigational product

administration even though it may have been present before the start of the study

signs, symptoms, or the clinical sequelae of a suspected interaction


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signs, symptoms, or the clinical sequelae of a suspected overdose of either

investigational product or a concomitant medication (overdose per se was not to

be reported as an AE/SAE)

the signs and symptoms and/or clinical sequelae resulting from lack of efficacy

were to be reported if they fulfilled the definition of an AE

Events that did not meet the definition of an AE included:

medical or surgical procedure (eg, endoscopy, appendectomy); the condition that

led to the procedure was an AE

situations where an untoward medical occurrence did not occur (social and/or

convenience admission to a hospital)

anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)

present or detected at the start of the study that did not worsen

the disease/disorder being studied, or expected progression, signs, or symptoms

of the disease/disorder being studied, unless more severe than expected for the

subject’s condition

Clinical AEs would have been described by diagnosis and not by symptoms when

possible (eg, upper respiratory tract infection, seasonal allergy, instead of runny

nose).

3.5.5.2 Serious adverse event

An SAE was any untoward medical occurrence that, at any dose:

a) resulted in death

b) was life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' referred to an

event in which the subject was at risk of death at the time of the event. It did not

refer to an event, which hypothetically might have caused death, if it were more

severe.

c) required hospitalisation or prolongation of existing hospitalisation

NOTE: In general, hospitalisation signified that the subject was detained (usually

involving at least an overnight stay) at the hospital or emergency ward for

observation and/or treatment that would not have been appropriate in the


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physician’s office or out-patient setting. Complications that occurred during

hospitalisation were AEs. If a complication prolonged hospitalisation or fulfilled

any other serious criteria, the event was serious. When in doubt as to whether

“hospitalisation” occurred or was necessary, the AE was to be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not

worsen from baseline was not to be considered an AE.

d) resulted in disability/incapacity; or

NOTE: The term disability meant a substantial disruption of a person’s ability to

conduct normal life functions. This definition was not intended to include

experiences of relatively minor medical significance such as uncomplicated

headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (eg

sprained ankle) which may have interfered or prevented everyday life functions

but did not constitute a substantial disruption.

e) resulted in a congenital anomaly/birth defect.

Medical or scientific judgment was to be exercised in deciding whether reporting was

appropriate in other situations, such as important medical events that may not have

been immediately life-threatening or resulted in death or hospitalisation but may have

jeopardised the subject or may have required medical or surgical intervention to

prevent one of the other outcomes listed in the above definition. These should also

have been considered serious. Examples of such events were invasive or malignant

cancers, intensive treatment in an emergency room or at home for allergic

bronchospasm, blood dyscrasias or convulsions that did not result in hospitalisation,

or development of drug dependency or drug abuse or reports of spontaneous abortion.

3.5.5.3. Vital signs

Blood pressure and heart rate were measured using SpaceLabs oscillometric

equipment, with subjects in a seated position; subjects remained seated for at least

3 min before vital signs were measured.

Abnormal findings that occurred during the defined time period for AE reporting and

that the investigator considered to be clinically significant were also to be recorded as

an AE or SAE. If the clinically significant abnormality was associated with a

diagnosis, the diagnosis was to be recorded on the CRF.


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3.5.6 MRI questionnaire

Subjects completed a questionnaire at screening, and before each MRI scan, to

confirm their suitability for the procedure.

3.5.7 Urine and breath tests

A urine test for drugs of abuse (cannabinoids, opiates, amphetamines, cocaine,

barbiturates and benzodiazepines) was done by the HMR Analytical Laboratory using

an enzyme immunoassay method.

Breath was tested for alcohol and carbon monoxide, using a calibrated Lion

alcometer, and a calibrated Bedfont Smokerlyser, respectively.

3.5.8 Height and weight

Body weight and height were measured using a calibrated scale.

For body weight assessments, subjects were asked to remove all outer garments,

including shoes, and to empty their pockets before the procedure. Weight was

measured in kg and recorded to 1 decimal place.

Body mass index was calculated, to confirm subject eligibility, using the following

equation: [BMI = Weight (kg) ÷ [Height (m)]2].

3.5.9 Appropriateness of measurements

The primary objective of the trial was to assess the effect of 14 days’ creatine

supplementation on muscle PCr levels, so it was appropriate to use 31P-MRS to

measure leg muscle creatine.

The secondary objectives of the trial were to assess the effect of 14 days’ creatine

supplementation on muscle energetics and cognitive function, and to assess the safety

and tolerability of 14 days’ creatine supplementation. So, it was appropriate to: use 31P-MRS to measure leg muscle creatine during exercise and recovery; do fMRI scans

of the brain; do cognitive function tests; measure vital signs; and assess AEs.


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The exploratory objective of the trial was to assess the effect 14 days’ creatine

supplementation on brain PCr levels, so it was appropriate to use 31P-MRS to measure

brain creatine.

3.5.10 Primary efficacy variable

The 31P-MRS measure of muscle PCr concentration at rest.

3.5.11 Drug concentration measurements

Not applicable.

3.5.12 Changes in the conduct of the study

There were no amendments to the protocol.

We initially planned to enrol 24 subjects in 2 groups of 12. The protocol allowed for

the enrolment of up to 8 extra subjects, in either group, or split between the groups.

After a per-protocol review of the unblinded data from 12 subjects in each group, the

sponsor decided to enrol a further 3 subjects into each group (to a total of 15 subjects

per group): 1 subject received the creatine supplement and the other 2 subjects

received matching placebo. 30 subjects were evaluated in total.

3.6 Data Quality Assurance

All data were securely stored within HMR.

Data were double-entered into a clinical database management system (ClinPlus

Version 3.3). Edit checks and generation of queries were done in ClinPlus.

Tabulations and listings were produced using validated, trial-specific SAS programs.

Quality control checks on the data were done by the Data Manager. The database

was locked after quality control checks demonstrated that the data were of suitable

quality.

The HMR Quality Assurance Department audited the trial report; that audit included

checks of correct reproduction of the statistical output in the report.

3.7 Data Analysis Methods

Further details of the statistical analyses are presented in the Statistical Analysis Plan

(SAP; Appendix 1.9).


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3.7.1 Determination of sample size

No formal sample size calculation was done. Based on previous studies [Smith et al.,

1998; Libri et al., 2012], 12 subjects per group (24 subjects in total) was considered to

be sufficient to meet the study objectives. However, after a planned unblinded review

of accumulated imaging data, the sample size was increased by 3 subjects per group

(6 subjects in total).

3.7.2 General considerations for data analysis

3.7.2.1 Interim analysis

No formal interim statistical analysis was done.

To confirm the adequacy of the sample size, accumulated imaging data from subjects

who had completed all study visits were reviewed in an unblinded manner by a

controlled group of individuals at the Sponsor to decide whether to enrol additional

subjects. After a per-protocol review of the unblinded data from 12 subjects in each

group (young athletes and ageing healthy), the sponsor decided to enrol a further 3

subjects into each group: 1 subject received the creatine supplement and the other

2 subjects received matching placebo.

3.7.2.2 Data displays

Data were summarised by group, and trial supplement received. The minimum set of

summary statistics for numeric variables was: n, mean, standard deviation (or

standard error), median, minimum, and maximum. 95% confidence intervals were

presented where appropriate for data interpretation.

Categorical data were summarised in frequency tables with n and percentage.

Summaries of variables included all recorded values.

The minimum and maximum values were presented with the same number of decimal

places as the raw data collected on the CRF (or to 3 significant figures for derived

parameters). The mean and percentiles (eg median, quartiles l and 3) were presented

using 1 additional decimal place. The standard deviation and standard error were

presented using 2 additional decimal places.


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3.7.2.3 Data handling conventions

Missing data

If a subject completed the treatment period but had missing data, those data were made

apparent in the listings. Missing data were not imputed for any analyses.

Data collected at unscheduled time points were listed, but not included in the

statistical analyses or data summaries.

If the time of AEs or a concomitant medication was missing, but the day was present,

derived time to/duration of event was calculated in days. If the date was missing,

then derived times were listed as missing.

Derived and transformed data

Baseline was the last value obtained before the first dose of trial supplement (Visit 1,

pre-dose or Screening, if not recorded pre-dose on Visit 1 (eg weight). Repeat values

before dosing were used.

Efficacy data

Further data handling conventions for imaging and cognitive data are provided in

Section 12.5 of the SAP (Appendix 1.9).

3.7.3 Study populations

3.7.3.1 Analysis populations and datasets

The following populations were identified:

Intention-to-Treat Population: all subjects who received at least 1 dose of trial

supplement and had had at least 1 post-baseline efficacy assessment

Per Protocol Population: all subjects who complied with all trial procedures and

restrictions, as described in the protocol and SAP

Safety Population: all subjects who were randomised and received at least 1 dose

of trial supplement

All analysis datasets were based on observed data.


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3.7.3.2 Disposition of subjects

The disposition of all subjects in the enrolled population was summarised including

number of subjects randomised, number completing the study by treatment, and

number withdrawn from the study.

All subjects who withdrew or were withdrawn from the study were to be listed by

treatment, with the reason for withdrawal.

A listing of analysis populations was provided.

3.7.3.3 Protocol deviations

Subjects who had a major protocol violation were to be identified and excluded from

the Per Protocol analyses as agreed by the biostatistician and principal investigator or

designee before unblinding. Deviations that would have resulted in exclusion from

the analysis included:

failure to meet inclusion and exclusion criteria

failure to take a sufficient number of sachets of trial supplements as required by

protocol

failure to reach exercise limit

In addition, specific data points may have been excluded from the Per Protocol

analyses as agreed by the biostatistician and principal investigator or designee before

unblinding. For example, a subject’s fMRI data may have been excluded due to

excessive head movement.

3.7.3.4 Demography and baseline characteristics

For each age group, the demographic and baseline characteristics of the subjects were

summarised by trial supplement, and overall, using descriptive statistics. The

demographics included age, gender, race, BMI, height and weight. Age, height,

weight and BMI were summarised as continuous variables (n, mean, standard

deviation, median, minimum, maximum), and race, gender and age group were

summarised as categorical variables, using frequency distributions.

3.7.4 Efficacy analysis and statistical methods

Efficacy data were summarised using the Intention-to-Treat Population as the primary

population.


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All endpoints in the data were visually inspected for gross outliers, and if considered

appropriate, a transformation was to be applied to normalise the data before analysis.

3.7.4.1 Primary efficacy parameters

3IP-MRS measure of muscle PCr concentration at rest.

3.7.4.2 Secondary efficacy parameters

Metabolic parame

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