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Significant, Real-World Evidence Confirms Previous Clinical Data On Improved Sleep Duration and Sleep Quality With REMfresh®, The First and Only Continuous Release and Absorption Melatonin (CRA-melatonin™)

SAN ANTONIO, June 10, 2019 /PRNewswire/ --

  • The 1,116 patient-reported outcomes (PRO) study, REMfresh Duration Validation (REMVAL), found that after taking 99 percent ultra-pure, continuous release and absorption melatonin (REMfresh®, CRA-melatonin™), the majority (78.8 percent) of patients involved achieved a sleep duration of greater than or equal to 6 hours (p<.0001), while more than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking CRA-melatonin for their sleep issues (p<.0001).
  • REMVAL provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong observed hypnotic effects of CRA-melatonin, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance and sleep quality.
  • A second PRO subset study, REMfresh Short Sleep Cohort Assessment (REMSS), involving 311 patients who reported sleeping four hours or less nightly from the REMVAL study, found that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001).
  • REMVAL and REMSS also provides validation of the results from the previously peer-reviewed and presented clinical study, REMAKT, which demonstrated that REMfresh mimics the body's own 7-hour Mesa Wave®, a natural pattern of melatonin blood levels during a normal night's sleep cycle and the 500-patient, peer-reviewed and presented REMfresh® Patient Reported Outcomes DURation (REMDUR) study, that demonstrated statistically significant improvements in sleep onset, sleep maintenance and sleep quality.

Physician's Seal, LLC®, innovators of REMfresh® (CRA-melatonin™), a clinically studied, drug-free, nonprescription, #1 sleep doctor-recommended melatonin sleep brand1 today announced significant, real-world data from a large group (1,116 patients) that supports and reinforces the benefits of REMfresh, the first and only continuous release and absorption melatonin (CRA-melatonin) formulation, which is designed to give patients up to 7 hours of sleep support. Comprehensive data from two recently completed patient-reported outcomes (PRO) studies provide further evidence of the observed hypnotic effects of REMfresh, demonstrating statistically significant improvements in sleep onset, sleep duration, sleep maintenance and sleep quality.

PRO studies of this kind, which more closely address real-world patient experience, are increasingly being recognized by regulatory authorities and academia in evaluating new therapies.  

The REMfresh Duration Validation (REMVAL) study provides further evidence of a correlative relationship between the 7-hour pharmacokinetic profile observed in the earlier clinical study, REM Absorption Kinetics Trial (REMAKT), and the hypnotic effects of REMfresh, observed in subsequent studies, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance, sleep quality and patient satisfaction. This latest study further validates the findings of past studies that have been presented and undergone peer review at major sleep conferences:  

  • REMfresh Patient Reported Outcomes DURation (REMDUR), the first, 500-patient, PRO study of this sleep brand, presented at the annual meeting for sleep specialists, SLEEP 2018, which demonstrated that more than 77 percent of patients achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh (p<.0001)2, and
  • REM Absorption Kinetics Trial (REMAKT), a pharmacokinetic study presented at SLEEP 2017 and 2018, which demonstrated that REMfresh mimics the body's own seven-hour Mesa-Wave® release profile, a natural pattern of melatonin blood levels during a normal night's sleep cycle.

An additional PRO subset study, part of REMVAL, called the REMfresh Short Sleep Cohort Assessment (REMSS), assessed improvements in sleep duration and sleep maintenance among 311 patients with morbid or extreme short sleep duration of 4 hours or less.

These two PRO studies (REMVAL and REMSS) were presented at SLEEP 2019, the 33rd Annual Meeting of the Associated Professional Sleep Societies (APSS), which is a joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society, held in San Antonio, Texas, from June 8-12.

"These latest findings provide further confirmation of the potential for nonprescription REMfresh to help address the public health issue of  the cumulative effects of sleep loss," said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology -- Head and Neck Surgery as well as Sleep Medicine, Founder and Principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician's Seal, LLC. "Based on a novel Ion Powered Pump® (IPP®) delivery system that provides a pharmacokinetic (PK) profile that more closely aligns with the body's own natural sleep pattern, REMfresh has demonstrated once again promising results and high levels of satisfaction in a real-world population of patients who have had chronic difficulties sleeping, providing up to seven hours of sleep support," said Dr. Brodner.

REMVAL Study Describes Improvements in Sleep Duration and Sleep Quality
The poster entitled, "Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality," reported findings provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong hypnotic effects of CRA-melatonin observed in subsequent studies and may offer a new low-dose, drug-free alternative to prescription hypnotics to treat chronic sleep disturbances.

The 1,116-patient REMVAL study was designed to obtain clinically relevant information about patients' past usage of melatonin and non-melatonin sleep aids, sleep patterns prior to taking CRA-melatonin, sleep duration before and after taking CRA-melatonin, frequency of CRA-melatonin usage, improvement in sleep onset, sleep maintenance and sleep quality after taking CRA-melatonin, and overall satisfaction with CRA-melatonin.

In the study, patients with sleep disturbances in the general population received a sample of REMfresh from their physicians and were invited to complete a 13-question online survey. After taking REMfresh, the majority (78.8 percent) of patients achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking REMfresh for their sleep issues (p<.0001).

REMSS Study Shows Improvement in Patients with Chronic, Extreme Short Sleep
The poster entitled, "Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study," highlighted findings from the REMfresh Short Sleep Cohort Assessment (REMSS), involving a cohort of 311 patients from the REMVAL study who reported sleeping four hours or less nightly. This cohort analysis was designed to obtain clinically relevant information from these patients experiencing morbid short sleep disturbances, including sleep patterns and melatonin usage before taking REMfresh, sleep duration before and after taking REMfresh, improvement in sleep onset, sleep maintenance and sleep quality after taking REMfresh, and overall product satisfaction.

Data from this cohort show that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). This increase from less than or equal to 4 hours to greater than or equal to 6 hours represents a major sleep duration upgrade in this group facing morbid sleep disturbances. More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Ninety-nine percent of the patients suffering with morbid short sleep (27.2 percent of whom had never previously tried a melatonin brand) reported that they were very likely or likely to continue using CRA-melatonin. These results provide real-world evidence that CRA-melatonin with its extended 7-hour pharmacokinetic  plateau time and benign safety-profile may be a practical baseline therapy to improve sleep duration and other key sleep parameters, including, sleep maintenance and sleep quality in this group of patients who have a higher risk of all-cause mortality.4˒5˒6˒7

Statistics & Data Corporation (SDC), a top-tier clinical data services provider, has independently determined that the number of participants in the study provides adequate power (>90%) to detect even small improvements in sleep outcomes. This high power, or probability of seeing statistically significant results if CRA-melatonin is truly working to improve sleep outcomes, applies to the overall study population (REMVAL) as well as the cohort of short sleepers (REMSS). SDC has subsequently independently validated the statistical results achieved, (e.g., p-values and statistical language).

The Increasing Appreciation of PRO Studies to Include Patient Experience 
Increasingly, there is an appreciation by the U.S. Congress, regulatory authorities and academia, of the substantive value that real-world patient experience brings to assessing new therapies. In addition to the traditional randomized, placebo-controlled trial studies, regulatory authorities are now incorporating the patient perspective in their decision making, including PRO studies. A PRO study is a measurement based on a report that comes directly from the patient about the status or change in their health condition and without amendment or interpretation of the patient's response by health-care intermediaries. PRO measures can be used to capture a patient's everyday experience outside of the clinician's office, and the effects of a treatment on the patient's activities of daily living.8˒9 Together, clinical measures and PRO measures can provide a fuller picture of patient benefit.

Chronic disorders of sleep and wakefulness affect an estimated 50-70 million adults in the United States.10 The cumulative long term effects of sleep loss have been associated with a wide range of damaging health consequences, including obesity, diabetes, impaired glucose tolerance, cardiovascular disease, hypertension, anxiety and depression.11 In terms of preventing health consequences, sleeping 6-8 hours per night consistently may provide optimal health outcomes.12

REMAKT Clinical Study Presented at Past Medical Meetings 
Pharmacokinetic data on REMfresh® was peer-reviewed and then presented in 2017 and 2018 at SLEEP, the Annual Meeting of the Associated Professional Sleep Societies LLC (APSS), and a joint meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS). 

The study, REM Absorption Kinetics Trial (REMAKT), was a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin). The study found that melatonin levels with REMfresh exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and then had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours. 

Analysis presented at SLEEP 2017 and 2018 showed that REMfresh builds upon the body of evidence from prolonged-release melatonin (PR-M), approved by the European Medicines Agency (EMA) in 2007 as a prescription drug for insomnia, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep onset and quality of life in patients aged 55 years and older compared with placebo.13 REMfresh was designed to overcome the challenges of continuous release and absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave®, a flat-topped hill with steep sides).14 There was the desirable fast time to reach the sleep threshold level, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave may help to improve sleep maintenance and morning alertness. 

Over 5,000 healthcare practitioners are estimated to have used REMfresh for their patients and about 320,000 patients are estimated to have purchased and used REMfresh. The continuing, rapid acceptance of REMfresh by patients is observable by several markers, including rapid sales growth and availability among major drug retailers.

About Statistics & Data Corporation (SDC)
SDC delivers top-tier clinical trial services to pharmaceutical, biologic, and medical device/diagnostic companies since 2005. With strategic scientific consulting and clinical data services (biostatistics, data management/EDC, and IRT/IWRS) expertise at our core, our services are scalable via our diverse and complementary strategic partnerships to provide full service clinical trial solutions.

About Nonprescription REMfresh®
REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of 0.5mg (Lite), 2 mg and 5mg (Extra Strength) UltraMel® melatonin. UltraMel melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician's Seal.

REMfresh caplets continuously release bioavailable, 99 percent ultra-pure melatonin over 7 hours, which may help a person fall asleep faster, stay asleep longer and experience quality sleep, such as deep sleep and REM sleep.

REMfresh was designed as a hydrogel matrix tablet with its patented, scientifically advanced Ion-Powered Pump® (IPP®) technology, pioneered by Physician's Seal. Initially, there is a rapid release of the melatonin from the surface of the tablet in the acidic environment of the stomach. As the tablet moves into the higher pH of the small intestine, where melatonin is unlikely to dissolve, acidic factors built inside the tablet maintain a lower pH within the tablet over 7 hours, to allow for continuous release and absorption of active melatonin into the intestines. This patented, novel delivery system was first presented at SLEEP 2017.

REMfresh is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh additive chemicals. The usual adult recommended dose is 1-2 tablets 30-90 minutes before bedtime. Specific dosing instructions found on the back of the box should be followed for proper use of supplements. REMfresh is available in 0.5mg (Lite), 2mg and 5mg (Extra Strength) versions.

REMfresh is available at Walgreens, CVS, Rite Aid, Amazon.com and www.REMfresh.com.

About Physician's Seal®
Physician's Seal® is the Innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin™) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician's Seal (PS), founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.REMfresh.com.

Physician's Seal's sister subsidiary, IM HealthScience® (IMH), is the innovator of the two medical foods IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD or recurring indigestion), respectively. IMH rounds out its line of digestive products with Fiber Choice®, a well-known, natural prebiotic chewable fiber that helps with regularity. In 2017, IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. Both PS and IMH are dedicated to developing products to address overall health and wellness in digestive health and sleep. The Physician's Seal and IM HealthScience advantage comes from developing products based on patented, targeted-delivery technologies, including IPP® (Ion-Powered Pump®) and SST® (Site Specific Targeting®) technologies. For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com, www.FDgard.com and www.FiberChoice.com.

Data Presented at SLEEP 2019 Poster Sessions:

Monday, June 10, 2019, 5:15-7:15pm

  • (Abstract 0398, Poster Board #135) Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study
  • (Abstract 0399, Poster Board #136) Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality

Visit Physician's Seal at booth 924 to learn more about REMfresh.

The abstracts are published in an online supplement of the journal, Sleep, which is available at https://sleepmeeting.org/wp-content/uploads/2019/04/SLEEP_42_S1-Website-Final.pdf.

1 Among primary care physicians with a certification in sleep disorders who recommended a brand of melatonin. IQVIA ProVoice Jan.-Feb. 2019 survey.
2 Seiden,D.J., Brodner, D.C., & Shah, S.M. (2018, June 2-6). Improvement in Sleep Maintenance and Sleep Quality with Ion-Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study (Abstract #0419). Poster presented at SLEEP 2018, Baltimore, Maryland.
3 Brodner, D.C., Shah, S.M. (2017, June 3-7). REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation versus a Same Strength Immediate-Release Formulation in Healthy Adults (Abstract #0396). Poster presented at: SLEEP 2017, Boston, Massachusetts.
4 Knutsen, K.L., Turek,, F.W., Patel, S.R., et al (2006). The u-shaped association between sleep and health: the 2 peaks do not mean the same thing.  Comment on Patel, SR, et al. Sleep, 29(7): 878-879.
5 Lubetkin,, E.I., & Haomiao, J. (2018). Burden of disease due to sleep duration and sleep problems in the elderly. Sleep Health, 4; 182-187.
6 Hafner M, et al. (2017). Why sleep matters-the economic costs of insufficient sleep: A cross-country comparative analysis, Rand Quarterly.
7 Ikehara, S, et al. (2009). Association of Sleep Duration with Mortality  from Cardiovascular Disease and other Causes for Japanese Men and Women: the JACC Study. Sleep, 32(3); 295-301.
8 U.S. Food and Drug Administration. Real World Evidence. Retrieved from https://www.fda.gov/scienceresearch/specialtopics/realworldevidence/default.htm
9 U.S. Food and Drug Administration. 21st Century Cures Act. Retrieved from https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/default.htm.
10 Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617
11 Cappuccio, F.P., D'Elia, L., Strazzullo, P., & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systemic review and meta-analysis of prospective studies. Sleep, 33(5):585-592.
12 Watson, N.F., Badr, M.S., Belenky, G., et al. (2015). Joint Consensus Statement of the American Academy of Sleep  Medicine and Sleep Research Society on the Recommended Amount of Sleep for the Healthy Adult, Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(6); 591-592.
13 European Medicines Agency.(2007). Assessment Report for CIRCADIN.
14 Brodner, D.C. & Shah, S.M. (2017, June 3-7). A Continuous Release Ion Powered Pump Melatonin Delivery System that Overcomes Challenges of Release and Absorption in the Intestines (Abstract #0385). Poster presented at: SLEEP 2017,  Boston, Massachusetts.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.REMfresh.com. Individual results may vary. 

Media Contact:
Gail S. Thornton
Worldview Communications
908-392-3420
gst@worldviewcomms.com

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