Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001245583
Ethics application status
Approved
Date submitted
19/02/2015
Date registered
13/11/2015
Date last updated
6/06/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to evaluate the effect of Flex-Aid beverage on frequency of nocturnal foot and/or leg cramps and its safety and tolerability
Scientific title
A blinded, randomized, cross-over study to evaluate the efficacy and tolerability of Flex-Aid in subjects with nocturnal foot and/or leg cramps
Secondary ID [1] 285786 0
Nil
Universal Trial Number (UTN)
N/A
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nocturnal foot and/or leg cramps 293675 0
Condition category
Condition code
Musculoskeletal 293973 293973 0 0
Normal musculoskeletal and cartilage development and function
Alternative and Complementary Medicine 294737 294737 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
As per below: there is no washout period between the end of period 1 and start of period 2.


In this study participants will receive three treatments, Treatment 1 (capsule), Treatment 2 (beverage) and Treatment 3 (beverage) to test the effect of Flex-Aid on stopping or reducing the night-time muscle cramps. Each treatment will be taken by mouth at home each night approximately 45 minutes before bedtime over 3 periods of time lasting 14 days each.

Each treatment may include a combination any of the following ingredients:
*Ginger extract (up to 750mg)
*Cinnamon extract (up to 500mg)
*Capsicum extract (ingredient in hot peppers, up to 38mg)
*8.3 grams of sugar from corn syrup
*Sugar
*Red food colouring

Treatment 2 and 3 (beverages) may smell like cinnamon, be the colour of soda and taste similar to atomic fireball candy or be very sweet. They may also be very hot and spicy.

Participants will be assigned by chance (like flipping a coin - random selection) to the order that they will receive the study treatments. Participants will be asked to take Treatment 1 (capsule), Treatment 2 or 3 (about 1/4 cup) up to 42 times during the study.


Approximately eighty (80) male and female subjects will be enrolled into the Run-in Phase of Period 1. Period 1 consists of two parts as follows:
Part 1 is a 7-day washout phase where subjects washout of existing treatments for nocturnal muscle cramps. Only subjects on treatments for leg cramps will be enrolled in the washout phase,
Part 2 is a 14 day single blind phase where subjects will self administer treatment 1 each day for 14 days. Approximately 48 eligible subjects who meet eligibility criteria will continue on to cross-over Periods 2 and 3 to achieve 40 subjects to complete the study (Treatments 2 & 3). Treatments 2 or 3 will be taken once every night for 14 days during Period 2; and the alternative treatment 2 or 3 once every night for 14 days during period 3. Eligible subjects will be randomized in a 1:1 ratio in cross-over periods 2 and 3.

Please note there is no wash-out period between treatments 2 and 3. Subjects will be provided all the necessary supplies and instructions for drug preparation as required at the scheduled study visit between Periods 2 and 3 (14 to 17 days). Treatments 2 and 3 occur consecutively.

The PI will appoint a qualified member of the study team to make telephone contact with each subject on Day 7 +/- 2 days in each study period to assess adherence to intervention protocols by asking the subject to indicate (and provide details concerning) whether or not the investigational product was consumed each night at the appropriate time during the preceding interval. Missed or inappropriately timed doses will be recorded. Subjects will also be asked to complete a daily study diary that includes time and date of dosing.
Intervention code [1] 290750 0
Treatment: Other
Comparator / control treatment
Capsule or beverage once daily at night.
Control group
Placebo

Outcomes
Primary outcome [1] 293751 0
Treatment difference (Flex Aid - Inactive treatment) in mean number of cramps/14 day period

This outcome will be assessed using:
Daily diary including a VAS scale that will measure the pain/intensity of the foot and/or leg cramps; Quality of Life Questionnaire (SF36); Sleep survey and CGI scale.
Timepoint [1] 293751 0
After each 14 day treatment:
Visit 3, End of Period 1; Visit 4: End of Period 2 Visit and Visit 5: End of Period 3/End of Study.
Primary outcome [2] 293752 0
No. of reported SAEs and unexpected AEs

Known AE's include: temporal headache, dizziness and flatulence. These AE's were considered probably related to Flex-Aid.

AE's will be noted in the patient diaries and captured during the study visits at each timepoint.
Timepoint [2] 293752 0
SAEs and AEs evaluated at each study visit:

Visit 2: Period 1, Run-In Day 1;
Visit 3: End of Period 1;
Visit 4: End of Period 2 Visit
Visit 5: End of Period 3/End of Study.

SAE's and AE's will be evaluated during telephone contact on Day 7 +/- 2 days in each study period.
Secondary outcome [1] 311753 0
Change from baseline in VAS pain/intensity assessments
Timepoint [1] 311753 0
Subjects to fill in VAS scale in daily diary to record pain/intensity if nocturnal foot and/or leg cramps they experience during each period 1, 2 and 3 of each treatment phase.
Secondary outcome [2] 311754 0
Change in severity of night/leg foot cramps from baseline in CGI scale
Timepoint [2] 311754 0
Visit 3: End of Period 1 Study Visit,
Visit 4: End of Period 2 Study Visit,
Visit 5: End of Period 3/End of Study Visit
Secondary outcome [3] 311755 0
Change from baseline in QOL SF-36 assessments
Timepoint [3] 311755 0
Visit 2: Run-in Day 1
Visit 3: End of Period 1 Study Visit,
Visit 4: End of Period 2 Study Visit,
Visit 5: End of Period 3/ End of Study Visit
Secondary outcome [4] 311756 0
Change in sleeping difficulty from baseline in Insomnia Severity Index assessments
Timepoint [4] 311756 0
Visit 2: Run-in Day 1
Visit 3: End of Period 1 Study Visit,
Visit 4: End of Period 2 Study Visit,
Visit 5: End of Period 3/ End of Study Visit

Eligibility
Key inclusion criteria
1. Male or female subjects who self-report having four (4) or more nights with at least one nocturnal-time leg and/or foot cramp within the last 4 weeks prior to Screening.
2. Subjects greater than or equal to 50 years of age at screening.
3. Negative urine drug and alcohol results at Screening and throughout the study.
4. Negative results at Screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV).
5. Males will either be surgically sterile or agree to use, through the duration of the study, one of the following approved methods of contraception: a male condom; a surgically sterile sexual partner; use of an intrauterine device by female sexual partner; a female condom; contraceptive sponge; a diaphragm; a cervical cap; an intravaginal system or oral, implantable, transdermal, or injectable contraceptives. Males will refrain from sperm donation throughout the duration of the study.
6. All females, regardless of childbearing potential, must have a negative serum beta human chorionic gonadotropin pregnancy test at Screening and negative serum or urine pregnancy test prior to treatment administration for each study period. Females of childbearing potential (i.e., not postmenopausal or surgically sterile [e.g., tubal ligation, hysterectomy, bi-lateral oophorectomy]) will be required to use a medically acceptable method of contraception starting from Screening throughout the duration of the study. A postmenopausal woman is defined as having spontaneous amenorrhea for at least 1 year with a serum follicle-stimulating hormone (FSH) value consistent with postmenopausal status as per PI judgment. Acceptable methods of contraception include a hormonal or non-hormonal intrauterine device; female condom; diaphragm/cervical cap; contraceptive sponge; a male sexual partner who agrees to use a male condom; a sterile sexual partner; or abstinence (subjects reporting abstinence who become sexually active while on the study must agree to use other additional barrier methods of contraception). The following contraceptive methods are acceptable only when used with an additional barrier method as mentioned above: birth control pills, birth control patches, vaginal ring, hormone under the skin, or hormone injections. Females will refrain from egg donation for the duration of the study.

Participants will be reassessed for eligibility by the Investigator at the end of Period 1, Run in. Participants who in the opinion of the PI do not continue to remain eligible will be removed from the study.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subjects with established disease/conditions that cause nocturnal leg cramps. These include:
a. Peripheral vascular disease;
b. Lower limb injury;
c. Progressive neuromuscular or neurologic disease;
d. Hemodialysis;
e. Simple muscle strain of lower extremity muscle(s) within the last 4 weeks;
f. Restless leg syndrome;
g. Hypocalcemia;
h. Diabetes.

2. Subjects with periodic limb movement disorders.
3. Subjects with peripheral neuropathy.
4. Subjects with gastroesophageal reflux disease (GERD).
5. Subjects suitable for inclusion in this study are expected to be receiving a variety of concomitant medications to treat other diseases/conditions. Subjects will be excluded if any of their other conditions/diseases are unstable (defined as subjects who have been hospitalized or required changes in their scheduled maintenance medications within the last 4 weeks) or are likely to result in changes in their scheduled maintenance medication (to avoid doubt this includes the addition of new medications or change of dose in an existing medication) or in hospitalization or in their ability to complete and/or participate in the study.
6. Subjects who are receiving statins should not be suffering from any musculo-skeletal adverse/side effects that may be related to this group of drugs.
7. Subjects who in the opinion of the Principal Investigator (PI), should not participate in this study.
8. Subjects who in the opinion of the PI are not able to dial into the IVRS system and complete diaries reliably. Subjects who do not comply with completion requirement to call into the IVRS or complete the diary while on study may be removed from the study at the discretion of the PI and the Sponsor.
9. Subjects that work overnight shifts and sleep during the day.
10. Subjects who have a food allergy to or dislike spicy foods or any the ingredients contained in the Flex-Aid (i.e., capsicum, ginger, and/or cinnamon).
11. History of significant hypersensitivity, intolerance, or allergy to any treatment component, food, or other substance, unless approved by the PI.
12. Individual who consumes more than 14 units of alcohol per week or who has a significant history of alcoholism or drug/chemical abuse within 1 year prior to the Screening (1 unit of alcohol equals 1/2 pint [285 mL] of beer or lager, 1 glass [125 mL] of wine, or 1 ounce [30 mL] of spirits).
13. Use of any drugs of abuse within the past 1 year prior to first treatment on Day 1, Run In, of Period 1 and throughout the duration of the study.
14. Use of any tobacco- or nicotine-containing products within 1 week prior to first treatment on Day 1, Run In, of Period 1 and throughout the duration of the study.
15. Participation in a clinical study within 30 days prior to the first treatment on Day 1, Run In, of Period 1.
16. Subjects who eat pickled or spicy foods or beverages throughout the study (including food containing chili peppers, including Tabasco or other hot sauces, ginger or cinnamon).
17. Injury or surgery to the lower limbs that in the opinion of the PI may impact the study results.
18. Female subjects who are pregnant or lactating.
19. Subjects taking prescription pain medications containing opiates (e.g., hydrocodone, oxycodone, codeine, etc.) or prescription NSAIDs that in the opinion of the PI could affect study results/data interpretation are prohibited from enrolling in the study.
20. Subjects taking gabapentin or related anti-epileptic drugs (AEDs) including but not limited to topiramate, carbamazepine, phenytoin, valproic acid, lamotrigine, and primidone are prohibited from enrolling in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each subject will be assigned a unique identification number upon Screening. Subjects who complete the study screening assessments and meet all the eligibility criteria will receive the corresponding treatment (i.e., Inactive treatment or Flex-Aid), according to a randomization schedule:

Period 1 – All subjects will receive treatment 1 capsules.
Periods 2 and 3 – subjects will be randomized at the End of Period 1 Study Visit to one of two treatment sequences consisting of treatment 2 and treatment 3.

Allocation of the treatment involves contacting the holder of the allocation schedule who is located at the central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The computerized randomization scheme will be created by a study statistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
80 participants recruited to period 1 to receive treatment 1, followed by a sub-group of 48 participants randomly allocated to receive treatments 2 and 3 in a crossover manner.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Determination of sample size:
Up to 80 male and female subjects will be enrolled into the Run-in Phase of Period 1 (Part 2). Approximately 48 eligible subjects will continue on to cross-over Periods 2 and 3 to achieve 40 subjects to complete the study (allows for an 11% drop out rate).

With a sample size of 20 completed subjects in each treatment sequence, the 2 x 2 cross-over design will have 80% power to detect a treatment difference (Flex-Aid – Inactive treatment) in mean number cramps/14 day period of -3.0 assuming the standard deviation of differences is 6.450, using a two group t-test with a 0.050 two-sided significance level. Assuming an 11% dropout rate, 48 subjects total will be randomized in cross-over Period 2 to achieve a total of 40 subjects to complete the study.

Efficacy Analysis

For the primary efficacy endpoint, the change from baseline in the number of cramps over a 14 day treatment period will be determined. A paired Wilcoxon signed rank test will be conducted to test for treatment effect at the 5% level of significance. Test for carryover and period effect will also be conducted at 10% and 5% respectively.
Other efficacy endpoints may be analyzed using the same method as appropriate.

Descriptive statistics- arithmetic mean (AM), standard deviations (SD), sample size (N), coefficient of variation (CV), median, minimum and maximum values will be calculated for the continuous efficacy endpoints (primary and exploratory) by treatment and time point.
Categorical efficacy endpoints will be summarized in frequency counts.

ANOVA may also be used to compare for treatment differences for the efficacy endpoints as appropriate.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
2/05/2016
Actual
Date of last participant enrolment
Anticipated
31/12/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 3235 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 10068 0
3086 - La Trobe University
Recruitment postcode(s) [2] 9015 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 290353 0
Commercial sector/Industry
Name [1] 290353 0
Flex Pharma, Inc.
Country [1] 290353 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Flex Pharma, Inc.
Address
Prudential Tower
800 Boylston St
24th floor
Boston, MA 02199
Country
United States of America
Secondary sponsor category [1] 289076 0
Commercial sector/Industry
Name [1] 289076 0
Neuroscience Trials Australia (trading as the Florey Institute of Neuroscience and Mental Health)
Address [1] 289076 0
245 Burgundy Street
Heidelberg 3084
Victoria, Australia
Country [1] 289076 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292055 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 292055 0
129 Glen Osmond Road
Eastwood
South Australia 5063
Ethics committee country [1] 292055 0
Australia
Date submitted for ethics approval [1] 292055 0
29/10/2014
Approval date [1] 292055 0
22/12/2014
Ethics approval number [1] 292055 0
CM9914

Summary
Brief summary
This study aims to evaluate the effects of Flex-Aid on the frequency of nocturnal foot and/or leg cramps when self-administered within 45 minutes before going to bed. We aim to assess the effect of Flex-Aid on quality of life and pain/intensity of the nocturnal foot and/or leg cramps as well as the safety and tolerability of Flex-Aid.

FlexPharma hypothesizes that the acetic acid contained in teh pickle juice of teh beverage works by activating certain ion channels (Transient Receptor Potential TRP) which are known to exist in primary sensory neurons in mouth, esophagus and gut, and that their activation upregulate inhibitory circuitry in the spinal cord to prevent repetitive firing of alpha motor neurons thereby relieving the cramp. This study investigates whether natural activators of TRP ion channels may relieve muscle cramps.
Trial website
Trial related presentations / publications
Public notes
The other site within Australia includes LaTrobe University.

Contacts
Principal investigator
Name 53266 0
Dr Sepehr Shakib
Address 53266 0
Level 5, East Wing
Royal Adelaide Hospital
North Terrace
Adelaide, SA 5000
Country 53266 0
Australia
Phone 53266 0
+61 8 8222 3924
Fax 53266 0
Email 53266 0
Sepehr.Shakib@health.sa.gov.au
Contact person for public queries
Name 53267 0
Dr Tina Soulis
Address 53267 0
Neuroscience Trials Australia
Florey Institute of Neuroscience & Mental Health
245 Burgundy Street
Heidelberg 3084
Victoria, Australia
Country 53267 0
Australia
Phone 53267 0
+61 3 9035 7158
Fax 53267 0
Email 53267 0
asoulis@unimelb.edu.au
Contact person for scientific queries
Name 53268 0
Dr Michael Szwanek
Address 53268 0
Celerion
621 Rose Street
Lincoln, NE 68502
USA
Country 53268 0
United States of America
Phone 53268 0
+1 402 437 4880
Fax 53268 0
Email 53268 0
michael.szwanek@celerion.com

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