Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04841499 |
| Other study ID # |
USAH-EH301 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 5, 2021 |
| Est. completion date |
July 15, 2021 |
Study information
| Verified date |
November 2021 |
| Source |
University of South Alabama |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to determine whether a short supplementation (7days) with BASIS™
increases the natural production of estradiol, measured in urinary waste. The overall
objective is to determine whether through increased estradiol levels, the undesirable
menopausal effects, assessed via questionnaires, are mitigated by a short-term
supplementation with BASIS™
Description:
Protocol Outline
Protocol Title: Effects of a seven-day BASIS™ supplementation on menopausal syndromes and
measurements of the urinary vitamin B3 and estradiol levels in pre-, peri- and
post-menopause.
I. Abstract
Context:
Nicotinamide adenine dinucleotide (NAD) is a derivative of vitamin B3 necessary to the
production of key hormonal regulators like estradiol. As we age, both NAD levels and
estradiol levels are reduced. Reduced estradiol levels have been associated with menopausal
syndromes. BASIS™ recent clinical outcomes have shown that this NAD precursor (BASIS™) boosts
declining NAD levels. In an n=1 study, repeated over 3 years, a short intake (<1week at
125mg/day) of over-the-counter nicotinamide riboside, one of the two active ingredients of
BASIS™, by a peri-menopausal 50-year-old female, resulted in the blunting of the undesirable
menopausal effects such as poor sleep and hot flashes. The other component of BASIS™ is
pterostilbene, a phytoestrogen, derivative of resveratrol. Phytoestrogens associate with the
protection of estradiol levels and relief of menopausal syndrome in women using
over-the-counter phytoestrogens. These outcomes and observations have prompted the proposed
study. We wish to establish whether the observed beneficial effects of nicotinamide riboside
and the reported beneficial effects of phytoestrogens on menopausal syndromes can work
synergistically with a product like BASIS™ and are observed more broadly in peri- and
menopausal women. Furthermore, we wish to establish whether remediation of symptoms can be
attributed to a naturally occurring increase in estradiol levels following the repletion of
NAD by BASIS™.
Objectives:
The first objective is to determine whether a short supplementation with BASIS™ increases the
natural production of estradiol, measured in urinary waste. The second objective is to
determine whether, through increased estradiol levels, the undesirable menopausal effects are
mitigated by a short-term supplementation with BASIS™.
Study Design:
Women suffering from undesirable menopause-related discomfort will be entered in this study.
Discomfort includes mood swings, hot flashes, bad sleep, and dry skin. The control cohort
will be composed of women who are pre-menopausal. All women entering the study will be given
a questionnaire before taking BASIS™ and once they have completed the 7-day supplementation.
They will also be asked to provide a urine sample at the time of each survey. The urine
samples will be analyzed for total estradiol content (estradiol, sulfate and glucoronate, and
estriol; all metabolites of estradiol) and for total vitamin B3 content.
II. Background and Significance/Preliminary Studies Menopause signals the end of the natural
reproductive potential and declining hormone levels for women; hormones such as estradiol.
Typically, a well-orchestrated sequence of estrogen, progesterone, and testosterone
production occurs each month with ovulation, but as we age, sex hormone levels start to
fluctuate and eventually decline significantly. This can last for upwards of 10 years prior
to the last menstrual cycle (peri-menopause).
Our brain, muscle, liver, skin, and fat cells all have hormone receptors, thus as changes
occur, they affect organ function on a cellular level. The climacteric syndrome is
characterized by several symptoms: hot flashes are the most common and reported by about 70%
of peri- post-menopausal women. Sleep disorders particularly decreased sleep quality, and
irritability are also commonly reported. Common biological mechanisms may explain in part the
relationship between hot flushes, sleep disorders, and irritability. For example, withdrawal
of hormones causes a change in the serotonin levels. The serotonergic system is implicated in
sleep, mood, and hot flashes. Tryptophan, an essential amino acid, is the precursor for
serotonin synthesis. Critically, tryptophan is also a precursor to nicotinamide adenine
dinucleotide, NAD[5]. NAD and its derivative NADPH are central cofactors to cellular
metabolism and cellular signaling with critical roles in aging. They are also co-substrates
in many biosynthetic pathways, including of estrogen-derived hormones such as estradiol.
Increased oxidative stress and declining NAD levels would affect the biosynthetic pathways
leading to estradiol[6]. Critically, estradiol levels steadily decrease over the course of
peri and post-menopause; a process which has been correlated to the occurrence and intensity
of menopausal symptoms
(https://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/the-e
xperts-do-agree-about-hormone-therapy).
Recent investigations in the field of NAD and NADP have unveiled a range of biosynthetic,
orally available precursors (nicotinamide riboside and nicotinamide mononucleotide), which
are able to boost NAD levels systemically[7]. This has led to a vast number of clinical
trials to investigate whether and if so by how much these precursors could boost circulating
NAD and alleviate age-associated disorders, such a metabolic dysfunction, obesity and
cellular aging. It has been suggested that oxidative stress, which increased NAD levels
appears to remediate, may also play a role in sleep disorders. While the outcomes remain
inconclusive in terms of clinical impact, these NAD precursors were shown to be safe and
well-tolerated by numerous types of participants at dosages as high as 1gram/day. One of
these trials included BASIS™. In addition to nicotinamide riboside, BASIS™ also includes
pterostilbene in its formulation. Critically, resveratrol and pterostilbene have a similar
chemical structure to the diethylstilbestrol and 17-beta estradiol and act as phytoestrogens,
protectors of estradiol levels. Furthermore, estrogen-like entities, phytoestrogen are
thought to enhance NAD function in cellular metabolism[8].
We hypothesize that as we age, a reduction in NAD levels and a shift in redox balance leading
and causing oxidative stress could correlate to a decrease in the production of estradiol.
This causation could be direct, by simply reducing the activity of the NAD(P) dependent
enzymes involved in the synthesis of estradiol and its precursors or indirect by
NAD-dependent protein post-translational modulation of gene expression pathways that impact
estradiol biosynthesis and function. A nutraceutical approach that combines increased levels
of NAD(P) to phytoestrogens like pterostilbene may be useful to preventive or at least
moderate the intensity of the menopausal syndromes controlled by reduced estradiol levels.
III. Study Aims
This is a pilot study that seeks to enroll up to 40 female individuals over 35 years of age.
The purpose of this study is to determine whether a short supplementation (7days) with BASIS™
increases the natural production of estradiol, measured in urinary waste. The overall
objective is to determine whether through increased estradiol levels, the undesirable
menopausal effects, assessed via questionnaires, are mitigated by a short-term
supplementation with BASIS™
IV. Administrative Organization
The study will be administered at the MCI.
V. Study Design
1. Experimental design of the study: This is a single-arm study for which non-peri and
non-menopausal women will act as a control cohort. We will seek for 25% of the recruited
cohort to be within the control group.
2. Study population general description: Any healthy women older than 35years of age can
partake in this study. However, individuals receiving hormone replacement therapy will
be excluded from the study.
3. Sample size determination and power analyses: This is a pilot study to establish the
proposed correlation between metabolites. Studies as small as 12 individuals have been
conducted to establish pharmacological roles for nicotinamide riboside as well as for
pterostilbene. Similar sample sizes have been employed to investigate the properties of
exogenous estradiol on sleep quality and hot flashes[9].
4. The outcomes of the study are three folds:
1. A correlation between levels of estradiol and bioavailability of circulating NAD
boosted by nicotinamide riboside will be established.
2. A correlation between NAD bioavailability and the occurrence and intensity of
undesirable menopausal symptoms will be established.
3. A correlation between the synergistic effect of NAD increase and pterostilbene on
the occurrence and intensity of undesirable menopausal symptoms by naturally
enhancing levels of estradiol will be established.
d. Study Assessments and Activities i. Following completion of the consent form, the
participants will be asked to fill a pre-supplementation questionnaire. They then will be
asked to provide a urinary sample after being given a urine sampling kit. Following this, the
participant will be provided with a small jar of BASISTM (supplies≥7days). The participant
will take 2 capsules of BASISTM once a day (total daily dose contains 250mg of nicotinamide
riboside and 50mg of pterostilbene). After 7 days, the participants will be asked to provide
a second urine in the urine sampling kit provided to them and fill in the same questionnaire.
ii. The questionnaire aims to evaluate the intensity and frequency of the most common
menopause-associated undesirable symptoms.
iii. Provide a schedule of all study assessments and subject activities, including a tabular
representation or timeline as applicable:
iv. Following completion of the consent form, the participants will be asked to fill in a
pre-supplementation questionnaire. They then will be asked to provide a urinary sample after
being given a urine sampling kit. Following this, the participant will be provided with a
small jar of BASIS™ (supplies>7days). The participant will take 2 capsules of BASIS™ once a
day (total daily dose contains 250 mg of nicotinamide riboside and 50 mg of pterostilbene).
After 7 days, the participants will be asked to provide a second urine sample in the urine
sampling kit provided to them and fill in the same questionnaire.
v. The questionnaire aims to evaluate the intensity and frequency of the most common
menopause-associated undesirable symptoms.
vi. Provide a schedule of all study assessments and subject activities, including a tabular
representation or timeline as applicable (visit chart in the full protocol)
VIII. Analysis Plan
This is a short-term metabolic study for which pharmacokinetics and pharmacodynamics outcomes
are anticipated. There will be no intention-to-treat methodology in the analysis. There will
be no sample stratification. The urine content of the NAD and estradiol catabolomes'
measurements will be presented as mean of biological replicates and 95% confidence interval
(CI) from all analyzed LC-MS measurements pooled from 2 technical replicates. For multiple
comparisons, ANOVA followed by posthoc test, i.e., Bonferroni correction for LC-MS and
Dunnett's or Tukey's for combination with questionnaire outcomes. Dependent t-tests and
repeated measures ANOVA will be used to evaluate within sub-groups variability. Statistical
analysis is performed using GraphPad PRISM 7.
DATA AND SAFETY MONITORING PLAN (DSMP):
INSTRUCTIONS FOR COMPLETION The purpose of this monitoring plan is to provide practical
guidelines for clinical monitoring procedures and to ensure proper auditing of the conduct of
research studies at MCI. This guidance will ensure the integrity of clinical data, compliance
with the protocol and regulatory guidelines. This study will be monitored by University of
South Alabama Mitchell Cancer Institute PI.
Study Title: Effects of a seven-day BASIS™ supplementation on menopausal syndromes and
measurements of the urinary vitamin B3 and estradiol levels in pre-, peri- and
post-menopause.
Risk Classification of the study:
For this study, there is intervention, and it is a minimal risk study.
The objectives of the monitoring are to:
1. Ensure subjects are being consented appropriately and prior to any study-related
procedures.
2. Verify subject eligibility.
3. Ensure all adverse events are reported in a timely manner.
4. Audit data against source documents.
5. Verify maintenance of regulatory documents.
6. Verify study drug accountability.
Type of Research Data or Events to be Monitored:
The study data manager and the coordinating PI will keep up-to-date data on a regular basis.
Accrual and safety data on this protocol will be reviewed by the PI, Data Manager, and Study
Coordinator. Meetings will be held monthly for 3 months then held quarterly thereafter until
completion of the study and End of Study meeting. The minutes of each meeting will be
provided for review by IRB at the University of South Alabama for their independent review.
All reports will be provided to the IRB of record and the study sponsor, Elysium Health.
Person(s) Responsible for Data Monitoring:
The purpose of monitoring is to ensure the rights of the human participants are protected,
the clinical trial is conducted in compliance with established guidelines and protocol as
well as to confirm that the data collected is accurate. Monitoring is performed by Dr. Marie
Migaud, that is assigned to the study and familiar with the Protocol, Informed Consent, SOPs,
etc.
Reporting Unanticipated Problems, Adverse Events, Protocol Deviations and Protocol
Violations:
Protocol deviations are to be documented by the PI (Dr Migaud) using the Protocol Deviation
Form and sent via e-mail to the IRB for review. Deviations that are considered major because
they impact subject safety or alter the risk/benefit ratio, compromise the integrity of the
study data, and/or affect subjects' willingness to participate in the study must be reported
within 10 calendar days of awareness of the event.
The PI will be responsible for reporting adverse events experienced by participants under
their care, untoward events occurring during the course of the study, protocol deviations and
protocol violation by completing Protocol Deviation Forms and acknowledgments for regulatory
filing to the sponsor. Protocol Deviations will be reported in monitoring reports:
- When the site is requesting a waiver or when a deviation from the protocol has occurred
using the process noted above.
- The Sponsor Team (Elysium Health) and the IRB, in turn, review and respond to the
deviation. At times, the Sponsor Team may request additional information from the site
to clarify the deviation or waiver request.
Procedures and Time Frames for Communicating Outcomes:
Monitoring of the primary objective will be performed and reviewed for impact. Additionally,
review of adverse events will occur monthly for the first 3 months and then quarterly
thereafter until completion of the study. Possible Adverse Events will be reviewed by the
Study's Clinical Principal and co-Principal Investigator
Emergency Actions:
Unblinding- This is not a blinded study.
Stopping Rules- This is a basic research study with no predefined endpoints other than data
acquisition to support or invalidate a hypothesis.
The pre-defined safety-efficacy stopping points for the entire study that would cause the
study to be suspended or terminated would be if there are concerns about the safety of the
participant or about data integrity.
