E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027311 |
E.1.2 | Term | Menopause flushing |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028812 |
E.1.2 | Term | Natural menopause |
E.1.2 | System Organ Class | 10041244 - Social circumstances |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027308 |
E.1.2 | Term | Menopause |
E.1.2 | System Organ Class | 10041244 - Social circumstances |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051775 |
E.1.2 | Term | Postmenopause |
E.1.2 | System Organ Class | 10041244 - Social circumstances |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this trial is to assess the efficacy of folic acid supplementation in terms of relief of the frequency and severity of vasomotor symptoms as compared to placebo
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
1. To study the efficacy of folic acid supplementation in terms of other menopausal symptoms as compared to placebo 2. To study the efficacy of folic acid supplementation on quality of life domains as compared to placebo 3. To explore the effect of folic acid in various prognostic subgroups: • Healthy women v cancer survivors (breast or endometerial cancer survivors) • Body Mass Index (BMI): ≤30 v >30
Exploratary Translational Study Objectives: 1. To assess the effect of folic acid supplementation on the blood level of serotonin and nor-adrenaline 2. To measure the correlation between clinical improvement, serum folate levels and blood levels of serotonin and nor-adrenaline 3. To assess the effects of folic acid supplementation on urine levels of nor-adrenaline metaboloite (5-HIAA) and serotonine metabolites (MHPG)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Experiencing ≥50 hot flushes per week, as quantified from daily patient Sloan Diary recordings for 7 days after consent and prior to randomisation 2. Being ≥40 and ≤70 years of age 3. Willing to participate in the trial and given informed consent |
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E.4 | Principal exclusion criteria |
1. Hormonal or non-hormonal treatment (including raloxifen) for menopausal symptoms within 8 weeks of enrolment 2. Baseline serum folic acid level which is above the normal laboratory range (3.1 to 20.0µg/L) 3. Smoking >5 cigarettes per day 4. Intestinal malabsorption e.g. celiac, tropical sprue or Crohn’s disease 5. Known chronic renal impairment or failure 6. Pernicious anaemia due to vitamin B12 deficiency 7. Taking the following drugs: • Non-steroidal anti-inflammatory drugs (NSAIDs) can interfere with folate metabolism • Cholestrol-lowering agents such as cholestryamine may decrease folic acid absorption • Chemotherapeutic agents such as fluorouracil and methotrexate can interfere with conversion of folate into tetrahydrofolate • Antibiotics such as chloramphenicol, trimethoprim and co-trimoxazole may inhibit dihydrofolic reductase • Sulfasalazine may decrease folic acid absorption • Anticonvulsants such as phenytoin, phenobarbital and primidone can interfere with absorption of anticonvulsants • Serotonin re-uptake inhibitors such as fluoxetine, venlafaxine, sertraline and paroxetine may ameliorate hot flushes • Serotonin disinhibitants such as mianserin and mirtazapine may ameliorate hot flushes • α2-adrenergic agonist such as yohimbine may aggravate hot flushes • α2-adrenergic antagonist such as clonidine may ameliorate hot flushes • Antacids containing aluminium or magnesium can interfere with folate metabolism • Preparations containing zinc such as vitamins or food supplements that may contain folic acid • Anticoagulant or thrombolytic therapy can interfere with folate assays
8. Therapies containing human anti-mouse antibodies (e.g. Trastuzumab and Bevacizumab) can interfere with folate assays 9. Alcohol consumption more than 14 units per week 10. Women with phaeochromocytoma or other medullary tumours or carcinoid syndrome 11. Known allergic reactions and/or hypersensitivity to folic acid 12. Women who are, in the opinion of the treating physician, unlikely to be able to give informed consent or successfully complete the trial intervention and procedures 13. Participation in another clinical trial within the last 4 weeks prior to enrolment
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in Hot Flush Score at 12 weeks from randomisation. A validated composite score B calculation based on frequency and severity as reported by patients in weekly Sloan Diaries
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the primary end point will be at the end of the treatment period. Treatment will cease at week 12. |
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E.5.2 | Secondary end point(s) |
1. Change from randomisation in Hot Flush Score at weeks 4, 8 and 12 as calculated using the composite score B 2. Change from randomisation in frequency of hot flushes (mild, moderate and severe) at weeks 4, 8 and 12 as calculated using frequency score B 3. The percentage of responders at weeks 4, 8 and 12; defined as a reduction in Hot Flush Score of ≥50% from randomisation as calculated using composite score B 4. Change from randomisation in longitudinal quality of life data as measured by the Utian Quality of Life Scale at weeks 4, 8 and 12 5. Change from randomisation in other menopausal symptoms using the Greene Climacteric Scale at weeks 4, 8 and 12 6. Investigate effects in specific prognostic subgroups of: • Healthy women v cancer survivors (breast or endometrial cancer survivors) • Body Mass Index ≤30 v >30 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of this end point will be at the end of the treatment period. Treatment will cease at week 12. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Compliance and Quality of Life |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The trial end date is deemed to be the date of last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The Trial Office will notify the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |