The Effects of Tualang Honey on Postmenopausal Women
Condition: Postmenopausal Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Despite evidence supporting the benefits of hormone replacement therapy (HRT), only 15% of
      postmenopausal women currently use HRT (1). The leading reasons why women refuse or
      discontinue HRT are fear of malignancy, side effects such as vaginal bleeding, weight gain,
      depressed mood, and breast tenderness, and social reasons such as regarding menopause as a
      natural transition, not as a disease that requires treatment. Millions of women expressed
      their concern on the safety of hormone replacement therapy since the data from the Women's
      Health Initiative (WHI) study was released, which reported an increased risk of
      cardiovascular disease, breast cancer, stroke and thromboembolic disease with conjugated
      equine estrogen plus medroxyprogesterone acetate compared with placebo (2). The study has
      also demonstrated that quality of life (3) and cognition (4) were no better in the HRT group
      than the placebo group. In view of these problems, women are increasingly turning to
      alternative therapies in an effort to manage their menopausal symptoms (1).

      Menopause is associated with decreasing sex steroid levels. The effect of menopause on
      circulating androgen levels has been studied by several investigators with variable findings.
      The levels of testosterone and androstenedione appear to show a small but significant
      decrease just before or within the first 2 years after menopause, with a decrease in
      testosterone amounting to approximately 15% (5,6). Unlike the abrupt decrease in estradiol
      levels associated with menopause, circulating testosterone, DHEA, and DHEAS levels decrease
      more gradually, beginning in the years before menopause and continuing thereafter (6,7). As a
      consequence, some women may experience symptoms of androgen decrease in the period before
      cessation of menses. By giving Tualang Honey to these postmenopausal women, it is postulated
      that the symptoms of androgen deficiency or menopausal symptoms should be reduced.

      The investigators have also reported that tualang honey given to ovariectomised rats, an
      animal model for postmenopausal states for two weeks significantly increased the free
      testosterone and progesterone plasma levels, but no significant effect was seen in the
      beta-estradiol level. There were significant increased in the thickness of vaginal epithelium
      and vaginal epithelial-muscular layers. Proliferation of the squamous epithelium with
      vacuolation of some of the squamous cells were noted in the honey treated animals implying
      that there were increased in mucopolysacharide content. Uterine weight, endometrial and
      circular muscle thickness were significantly increased in honey treated animal with cystic
      changes noted over the glands (8).

      To date, there are no clinical studies looking at the effects of Tualang Honey on
      perimenopausal women. In view of the initial evidence that it is a phytoestrogen from animal
      studies and has androgenic properties as well, it should have a beneficial effect to these
      women in terms of improvement in their menopausal symptoms, changes in their endogenous
      hormonal profile and increase in bone mineral density.
    

Detailed description: 
      OBJECTIVES

        1. To evaluate the safety profile of honey in term of haematological and biochemical
           profile

             -  haematological function

             -  liver function

             -  renal function

        2. To assess the changes in cardiovascular parameters

             -  blood pressure

             -  waist circumference

             -  total cholesterol

             -  high density lipoprotein

             -  low density lipoprotein

             -  fasting glucose

        3. To assess the effects on hormonal level

             -  follicular stimulating hormone (FSH)

             -  luteinizing hormone (LH)

             -  testosterone

             -  estradiol

        4. To assess the effects on bone density through bone densitometry (DEXA) scan measurement.

           Description of Methodology Study Subjects

           This is a randomized, prospective, clinical study to evaluate the effects of honey in
           comparison with hormone replacement therapy (HRT). Subjects will be confined to
           postmenopausal women. The study period will be four months, 41 subjects will be
           recruited for each group. A total of 82 patients will be recruited in this study.
           Eligible subjects consenting to participate will be randomly assigned to one of the two
           groups:

           GROUP 1: Subjects receiving 20 g/day of Tualang Honey GROUP 2: Subjects receiving
           hormonal replacement therapy (Femoston)

           Study Schedule

           About 10 ml of fasting blood samples will be collected for hormonal profiles at baseline
           and at the end of the study. The hormones to be assayed will be serum follicle
           stimulating hormone (FSH), Luteinising Hormone (LH), estradiol and total testosterone.
           Blood will also be taken for safety profile (haematology, liver function test and liver
           function test) and for cardiovascular parameters such fasting lipids and fasting blood
           sugar. Bone density will be check using Dual Energy X-ray Absorptiometry (DEXA) at
           baseline and end of the study. Subjects will be thoroughly examined by Medical
           Specialists who are part of the Clinical Trial Team at every 2-monthly visit.

           SAMPLE SIZE ESTIMATION

           The calculated sample size for the study is based on a standard statistical approach,
           often called as power calculations, which is widely used to calculate sample size in
           clinical trials.

           The formula is as below:

           N = p1 x (100 - p1) + p2 x (100-p2) x f (α, β)

           (p1 - p2) 2

           In our pre-clinical trial (ovariectomised rat), about 40% increase in mean testosterone
           level was observed among the low dose group. Assuming a similar increase of ~10% is also
           obtained in the placebo group, and at a power of 80%, the calculated number of subjects
           per group would be 29. Taken into consideration that there will be about 40% drop-out
           rate, each treatment group would therefore be 41 subjects.

           Actual calculation:

           Set p1 = 40; p2 = 10; α β = 7.9

           N = 40 (100-40) + 10 (100-10) x 7.9 = (40 x 60 + 10 x 90) x 7.9 (40-10)2 900

           = 29

             -  40% dropout = 29+ 12 =41 subjects per treatment arm There will be 2 groups, 41
                subjects X 2 groups = Total of 82 patients need to be recruited.

           STUDY PROCEDURE Pre study screening

           Informed consent

           Healthy females, who have been considered for entry into the study, will be informed
           about the study and asked if they would like to participate. Subjects agreeing to
           participate must provide informed consent prior to any study specific assessments or
           procedures being informed.

           The study will be fully explained to the subject by the investigator. The investigator
           will provide the subject with a comprehensive explanation of the proposed treatment
           including , but not limited to, the nature of the therapy, alternative therapies, any
           known previously experienced adverse reactions, the investigational status of the tested
           extract and also the study aims, methods, anticipated benefits and potential hazards of
           the study, including any discomfort they may experience as a result of study
           participation. A summary of this information will also be provided to the subject in
           writing.

           The subject must have the opportunity to clarify with the Investigator any issues they
           did not understand and if necessary, ask further questions. The subject must be given
           adequate time to consider whether they wish to participate in the study. The subject
           must be informed that they are to withdraw consent at any time, without penalty or loss
           of benefits to which the patient is otherwise entitled.

           The investigator will obtain the subject's informed consent. The person, who obtains the
           informed consent, signed and dated the informed consent form. If this person is not the
           investigator, then the investigator must also sign and personally date the written
           informed consent form. A copy of the patient information sheet and the signed consent
           form must be provided to each subject.

           Screening procedures

           The following assessments were performed for all subjects during the screening process
           and recorded in the Clinical Record Form

             -  Subject initials

             -  Demographic details including weight and height

             -  Physical examination and investigations including pelvic ultrasonography and DEXA

             -  Brief medical history relating to past and current illnesses

             -  Concomitant medication

             -  Collect fasting blood sample for the following laboratory evaluations.

           Patient randomisation/blinding

           Subject will be randomized using Block Randomization. The assignment of Tualang Honey
           will be blinded to patients using ID numbers.

           Patient's withdrawal

           The investigator may cease study treatment and withdrew the subject or the subject may
           withdraw herself from participation in the study at any time. The reason for the
           withdrawal of a patient will be recorded in the CRF. Subject will be followed-up for a
           minimum of 30 days following the last dose of study drug.

           Possible reasons for patient withdrawal include:

             -  The need to take medication, which may interfere with study measurements.

             -  Patient experiences an intolerable / unacceptable adverse event

             -  Patient exhibits non-compliance with the protocol

             -  Patient unwilling to proceed and / or consent is withdrawn

             -  Investigator withdraws patient for reasons unrelated to the study drug (e.g.
                undercurrent illness)

           SAFETY ASSESSMENT

           Protocol specific clinical assessment

           Screening day and end of treatment

           Demographic details will be recorded at screening. The subject's body weight, blood
           pressure will be measured at 2 monthly periods.

           Medical history and adverse events

           At the screening visit, a physical examination will be conducted to determine the
           patient's current medical conditions and past clinically significant events. This
           includes all events that have occurred within the last three months and any other
           earlier event related to the inclusion and exclusion criteria or the subject's disease.
           This will be recorded at the screening visit. Throughout the study period, subject will
           be directly questioned about the occurrence of any new signs and symptoms and any
           changes from baseline will be recorded as an adverse event. Diary will be given to the
           patient to chart the proper timing and date for ingestion of honey.

           A physical examination will be repeated at the end of the treatment and exit evaluation
           to assist in determining if there had been any changes to the patient's health during
           the study period. Physical examination details will not be recorded in the CRF, unless
           there are changes from the baseline that warrant recording as a new adverse event or
           change to an existing adverse event.

           Vital signs

           All visits

           Vital signs (supine blood pressure, pulse rate) will be recorded at every visit. Patient
           is supine or semi-recumbent for five minutes prior to evaluating vital signs.

           Concomitant medication

           Concomitant medication included all co-administered drugs and treatment such as
           analgesics, tonics, herbals or traditional medicines and vitamin and/or mineral
           supplements. All concomitant medication taken within 7 days prior to commencement of
           study drug administration and for the duration of the study will be recorded in the CRF,
           including indication, dose, frequency, date and route administered.

           SAFETY REPORTING

           Adverse event definition

           An adverse event (AE) is defined as any untoward medical occurrence (including
           clinically significant laboratory findings) in a patient or clinical investigation
           subject administered a pharmaceutical drug, and which did not necessarily have a causal
           relationship to the treatment. Adverse event may include:

             -  The significant worsening of the disease or symptoms of the disease under
                investigation following administration of the drug

             -  Any undercurrent illness with an onset after administration of the drug

             -  Exacerbation (i.e. increase in frequency or intensity) of a pre-existing condition
                or event

           Serious adverse event definition

           A serious adverse event (SAE) is defined as any untoward medical occurrence that at any
           dose:

           Results in death

             -  Is life-threatening. A ' life-threatening' adverse event refers to an event, which
                puts the patient at risk of death. It does not refer to an event, which
                hypothetically might cause death if it is more severe.

             -  Requires in-patient hospitalization or prolongation of existing hospitalization.
                Hospitalization is defined as the patient being hospitalized overnight, or the
                patient's hospital stay being prolonged for at least an additional overnight stay.
                Hospital admissions for elective surgery, for social reasons or for normal disease
                management procedures that are not the result of the worsening of an underlying
                condition will not be considered a serious adverse event.

             -  Results in persistent or significant disability/incapacity

             -  Is a congenital anomaly/birth defect

             -  Is a malignancy

             -  Is the result of an overdose? An important medical event, which jeopardizes the
                patient and may require medical or surgical intervention to prevent one of the
                above outcomes from occurring.

           STATISTICAL ANALYSIS:

           Data will be entered, cleaned and analyzed using SPSS version 12. Means and standard
           deviations for numerical variables and frequency and proportion for categorical
           variables will be reported along with histogram or bar chart if necessary.

           For univariable analysis the independent t-test and one way ANOVA will be used to
           compare numerical outcome variables among the three treatment groups and chi square for
           categorical outcome variables.

           For mutivariable analysis, repeated measure ANOVA will be used for analysis to adjust
           for confounding variables. Level of significance is set at 5% and results will be
           presented with 95% confidence intervals.
    

Intervention name(s): Tualang honey
Intervention type(s): Drug
Intervention description(s): This was a randomized, prospective, clinical study to evaluate the effect of Tualang honey in comparison with HRT. Subjects will be confined to healthy postmenopausal women who were naturally menopause for more than one year. The study period was four months. A total of 79 patients were recruited.
Group 1: Subjects receiving 20 g/day of Tualang honey. The honey used was from a single batch honey supplied by Federal Agricultural Marketing Authorities (FAMA), Malaysia, evaporated by FAMA to achieve a water content of about 20%, submitted to Sterile Gamma company at Shah Alam, Selangor for sterilization at 25 kGy and packed in 20 g sachet in collaboration with School of Pharmaceutical Sciences laboratory.
Group 2: Subjects receiving hormonal replacement therapy (Femoston®), also known as Femo conti 1/5 (contain 1 mg Estradiol valerate and 5 mg Dydrogesterone) supplied by Solvay Pharma Malaysia.
Other intervention name(s): Femo conti 1/5 (contain 1 mg Estradiol valerate and 5 mg Dydrogesterone)
Intervention MeSH terms: Estradiol; Dydrogesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: Tualang honey; HRT; safety profiles; cardiovascular parameters; hormonal levels; bone changes; postmenopausal women