| 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 |
| People with low Vitamin D levels circulating in their blood |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10047626 |
| E.1.2 | Term | Vitamin D deficiency |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 principal objective of this study is to assess whether giving 6 months of high dose Vitamin D3 (200,000 units or 100,000 units once every six to eight weeks) oral liquid drops together with daily maintenance Vitamin D3 1000 units tablets in south Asians with low vitamin D (25OH vitamin D3 <25nmol/l) improves markers of insulin function (specifically a marker known as HOMA1-IR, by greater than 0.36 units) compared to south Asians with low Vitamin D levels who take just maintenance 1000 units Vitamin D3 per day. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to assess whether giving 6 months of high dose Vitamin D (200,000 or 100,000 units every 6 to 8 weeks, followed by daily 1,000 units) in south Asians with low Vitamin D levels (25OH vitamin D3 <25nmol/l) improves other markers of (a) insulin function (known as HOMA1-IR), (b) glucose levels (known as fasting and two hour plasma glucose) and (c) HbA1c compared to south Asians with low Vitamin D levels who take 1000 units per day only. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| All sub-studies are optional and will require written informed consent prior to initiation. (1) Biomarker analysis (31/11/2010) included in proctocol v1.0 Certain proteins known as biomarkers are associated with an increase/ decreased risk of diabetes and are usually not routinely measured in clinical practice. These can include adiponectin, leptin, interleukin-6, tumour necrosis factor, highly sensitive CRP, pro-insulin, c-peptide. We wish to investigate if the 6 month of high dose vitamin D intervention (vs. control) creates a less adverse profile of these biomarkers or other biomarkers and reduces the future risk of diabetes. Tests will be performed on stored samples and may include some of the above named biomarkers or newer ones. This does not include genetic studies. (2) Area under the curve using frequently sampled oral glucose tolerance tests 01/09/2011. Included on version 1.1 of protocol. We wish to perform more glycaemic tests during the OGTT. Blood tests are already taken at 0 and 120 minutes for the OGTT. We will be taking further tests at any of 30, 60 and 90 minutes as well. To avoid having 5 separate blood tests, the best option is to place an intravenous cannula in to the patient for the two hours, which gives continual access to the blood circulation. Using this extra information we can calculate glucose and insulin area under the curve at baseline (0 months) and follow up OGTTs (6 months) and allow us to see the effect of high dose vitamin D intervention compared to control. (3) Measuring accurate physical activity levels (01/09/2011) - included in protocol version 1.1 Participants may be asked to have their physical activity levels objectively measured at baseline and after follow-up using a tri-axial accelerometer. Our objective is to see whether high dose Vitamin D replacement increases physical activity versus the control group. This may be measured using a triaxial Actigraph GT3X model (or newer model if available in department at the time) which incorporates an inclinometer to provide postural data on subject position (lying or sitting). Participants will be asked to wear the accelerometer on a waistband (in the right anterior axillary line) for up to seven consecutive days during waking hours. A total of 4 days valid wear will be required to count as a valid recording and a ‘valid day’ will consist of at least 10 hours of accelerometer movement data. The accelerometer will record movement data every 5 seconds (i.e., 5 second ‘epoch’). Prolonged periods of no movement, that is, strings of ‘0’, will be assumed to be non-wear time and will be excluded. Participants will be given an information leaflet explaining how to use the device (attached). Including a time sheet of when they wore it. To encourage participants to remember to wear the accelerometer they may be asked to write cards to place in convenient locations around the home. We may send them reminders (including phone calls or text messages) reminding participants to wear the device and return it once the time period is finished using pre-paid envelops addressed to our department. |
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| E.3 | Principal inclusion criteria |
| Inclusion criteria: We will include the following people if they meet all criteria: 1. 25-75 year old south Asian (Bangladeshi, Indian, Pakistani, Sri Lankan or other South Asian country) men or women. 2. A low vitamin D level (defined by a specific marker, 25(OH)VitD <25 nmol/L) 3. Insulin resistance, defined as HOMA1-IR ≥ 1.93. |
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| E.4 | Principal exclusion criteria |
| We will exclude people if they have any one of the following: 1. Those who have been told by a doctor they have diabetes (Type 1 or 2). 2. Those who developed new diabetes (WHO 1999 diagnostic criteria) detected on the Screening Visit fasting glucose test (such participants will be offered a confirmatory test to determine if they have diabetes with an oral glucose tolerance test) or the oral glucose tolerance test at Baseline Visit. Any individual with new diabetes will have follow up arranged with a doctor. If the confirmatory test does not show new diabetes, the participant will is elegible to re-enter the study. 3. HbA1c ≥ 6.5% which now diagnostic of diabetes. 4. Pre-existing calcium and/or Vitamin D tablets (D2 ergocalciferol or D3 cholecalciferol) / therapy (e.g. intramuscular injections, oral liquid preparations) or previous adverse reaction to Vitamin D (D2 or D3). Any individual who has previously been on these therapy must have been off Vitamin D/ Calcuim for at least one-two months. 5. Pregnancy or breast feeding females, or actively trying/ intending to become pregnant during the planned six month trial. 6. A history of known or newly detected hypercalcaemia or hypocalcaemia, hyperparathyroidism (that induce high calcium levels), kidney stones or other kidney problems/ low kidney function (eGFR<60 = CKD stage 3, 4 or 5) or known history of liver problems/ disorders. Also granulatamous conditions which may influence vitamin D and calcuim will be excluded. 7. A history of known bone diseases (e.g. osteoporosis, osteomalacia, osteopetrosis) or muscle diseases. People with a history of fractures and falls will also be excluded. 8. Any participant discovered to have new kidney/ liver/ bone or other health problems discovered during Screening or Baseline visit. Such individuals will have approprioate follow up organsied. A raised PTH will be considered in the clinical context of symptoms, ALP and Vitamin D level (i.e. may or may not be excluded). 9. Terminal illness, malignancy or physical inability to give consent (not language barriers). 10. Taking medications which may interfere with Vitamin D metabolism (anti-convulsants as as phenytoin, carbamazepine; primidone and barbituates), potentially leading to other problems (bendroflumethiazide, digoxin) or influencing hyperglycaemia/ insulin resistance (e.g. oral corticosteriods) 11. Participants unable to commit time for the six month study (e.g. holiday abroad, work commitments). 12. Actively taking part in another interventional study (e.g. medication, lifestyle RCTs); observational and cross sectional studies are still permitted. 13. People with an allergy to nuts (as Vitamin D liquid preparations/ oil plaecbos) may contain small amounts of peanut oil. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| This study will test the hypothesis that 6 months of periodic high dose Vitamin D3 replacement (200,000 or 100,000 units cholecalciferol, oral liquid drops at 6 to 8 week intervals) followed in-between by daily 1000 units, decreases insulin resistance by HOMA2-IR ≥ 0.36, in comparison to control, standard maintenance dose Vitamin D3 1000IU/ day for 6 months, in south Asians with both Vitamin D deficiency (defined as 25 Hydroxy vitamin D < 25nmol/l) and insulin resistance (defined as HOMA-IR≥ 1.93). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All evaluations will occur once all participants have gone through the 6 months of the randomisation control trial. It is likley this will be at the end of 2013 or throughout 2014. |
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| E.5.2 | Secondary end point(s) |
| 1) To investigate the effects of 6 months of periodic high dose Vitamin D3 replacement (200,000 or 100,000 units, cholecalciferol oral liquid drops, at 6 to 8 week intervals) followed in-between by daily 1000 units, in comparison to control, Vitamin D3 1000IU/day for 6 months, in insulin resistant, Vitamin D deficient south Asians for improvements/ changes in: a) Fasting glucose, 2 hour plasma glucose and HbA1c b) Area under the curve for glucose and insulin (optional sub-study) c) change in Physical activity level (optional sub-study) 3) To assess the safety and tolerability of 6 months high dose Vitamin D replacement in UK South Asians within the confines of an established clinical research network. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All evaluations will occur once all participants have gone through the 6 months of the randomised control trial. It is likley this will be at the end of 2013 and throughout 2014 |
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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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 |
| Vitamin D administered at 8000 Iu/day. Higher doses have been used, but not 8,000IU specifically |
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| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Vitamin D3 (colecalciferol) 1000 IU per day for 6 months (UK national guidelines) |
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 end of the trial will be at the six month final visit after the study entry. Please note, there will be a telephone conversation with all the participants after 1 month study exit - this is a general courtesy conversation where any issues can be discussed. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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