Can vitamin D supplementation in patients with Crohn's disease improve symptoms as an adjunct therapy

ISRCTN	ISRCTN15717783
DOI	https://doi.org/10.1186/ISRCTN15717783
ClinicalTrials.gov (NCT)	NCT03718182
Clinical Trials Information System (CTIS)	2018-003910-42
Protocol serial number	40194
Sponsor	University Hospitals Birmingham NHS Foundation Trust
Funder	NIHR Academy; Grant Codes: ICA-CDRF-2017-03-083

Submission date: 28/01/2019
Registration date: 01/03/2019
Last edited: 14/04/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
About half to three-quarters of people with Crohn’s Disease may develop vitamin D deficiency (very low levels of vitamin D in the body). Vitamin D is very important to help maintain healthy bones. Recent research has found that for people with Crohn’s Disease, having normal levels of vitamin D might also help to improve the symptoms of their disease. Despite this vitamin D levels are not routinely checked for people with Crohn's Disease. There are many different doses and types of vitamin D available on prescription and over the counter but there is no standard treatment for vitamin D deficiency in Crohn's Disease. The aim of this study is to compare two different doses of vitamin D capsules to treat vitamin D deficiency in adults with Crohn's Disease. The aims of the study are to:
Understand what proportion of people with Crohn's Disease have vitamin D deficiency at the end of the winter and during the summer months.
Understand any specific factors that might contribute to vitamin D deficiency in people with Crohn's Disease.
Find out if it is possible to carry out the study with a large number of people to see which dose of vitamin D is best at treating vitamin D deficiency in people with Crohn's Disease

Who can participate?
Vitamin D Screening studies: Adult patients with Crohn’s Disease who have their usual care at one of the participating hospitals
Vitamin D Supplementation trial: Adult patients with Crohn’s Disease who have been found to have vitamin D deficiency in the winter vitamin D screening study

What does the study involve?
Vitamin D Screening studies: Participants have a finger-prick blood test to measure their vitamin D levels. They also answer questions about their diet and lifestyle that might influence their vitamin D levels.
Vitamin D Supplementation trial: All participants receive a vitamin called D3 (cholecalciferol). The capsule is taken once a day by mouth. Participants in one group get a different treatment than participants in another group. There are two treatment groups: one group receive vitamin D3 400 iu, one capsule daily for24 weeks. The other group receive vitamin D3 3,200 iu one capsule daily for 12 weeks and then vitamin D3 800 iu one capsule daily for 12 weeks. A number of blood samples and a stool sample are taken to monitor the safety and effectiveness of the treatment. Blood tests and stool samples are taken at the start, after 12 weeks and then at the end of 24 weeks. Participants complete questionnaires at the start of the study and at the end of 24 weeks and keep a diary of when they have taken their vitamin D capsules each day. It is expected that each study appointment may take up to 40 minutes to complete. Appointments are carried out at the hospital participants usually attend for their Crohn's Disease follow-up.

What are the possible benefits and risks of participating?
Vitamin D Screening studies: It is hoped that the results from the study will help doctors and patients in the future when making decisions about treatment. There should not be any risks involved in taking part in the Vitamin D Screening Study. Some people may find the finger-prick blood test uncomfortable. Four large spots of blood are needed for the test. If it is difficult to get enough drops of blood from the first finger prick it may need to be repeated. The researchers will try to take the samples from the least sensitive part of the fingertip.
Vitamin D Supplementation trial: It is hoped that the results from the study will help inform a large study that will help doctors and patients in the future when making decisions about treatment for people with Crohn's Disease. Both treatments have been shown to treat or prevent vitamin D deficiency, but it cannot be guaranteed that either treatment will make any difference to the symptoms of Crohn's Disease. The main risk of taking any vitamin D supplement is developing too much calcium in the blood (hypercalcaemia). Hypercalcaemia may also lead to calcium in the urine (hypercalciuria). This risk is classed as 'uncommon' but if this happened the main symptoms would be: nausea, vomiting, passing large amounts of urine, loss of appetite, weakness, apathy, thirst, constipation. For this reason calcium blood levels will be checked at the beginning of the study to ensure they are normal, and at the 12 week and 24 week appointments along with other safety blood measures to ensure they remain within safe limits. Rarely some people report developing a rash when they take a vitamin D capsules. Participants will need to have three sets of blood tests over the whole study duration. Some people may find these uncomfortable and there may be some bruising afterwards but samples will be taken by an appropriately trained person.

Where is the study run from?
1. Queen Elizabeth Hospital Birmingham (UK)
2. Birmingham Heartlands Hospital (UK)
3. Good Hope Hospital (UK)

When is the study starting and how long is it expected to run for?
Vitamin D Screening will be starting in March 2019 and will continue for about 2 months. The participants in the vitamin D supplementation study will be in the study for a total of 36 weeks.

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Dr Jane Fletcher
jane.fletcher@uhb.nhs.uk

Contact information

Dr Jane Fletcher
Scientific

University Hospitals Birmingham
Queen Elizabeth Hospital
Mindelsohn Way
Edgbaston
Birmingham
B15 2WB
United Kingdom

ORCID ID	0000-0001-5033-8278
Phone	+44 (0)121 371 4561
Email	jane.fletcher@uhb.nhs.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment, Screening, Drug, Dietary
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Can vitamin D supplementation in patients with Crohn's disease improve symptoms as an adjunct therapy: D-CODE feasibility study
Study acronym	D-CODE Feasibility Study version 1.0
Study objectives	Treating vitamin D deficiency with oral supplementation in people with Crohn’s Disease may help to improve the symptoms of their disease.
Ethics approval(s)	Current ethics approval as of 20/09/2019: Approved 08/03/2019, Newcastle and North Tyneside 2 Research Ethics Committee, NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, Tel: +44 (0)207 1048082, Email: nrescommittee.northeast-newcastleandnorthtyneside2@nhs.net, ref: 19/NE/0019. Previous ethics approval: Newcastle and North Tyneside 2 Research Ethics Committee, NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, Tel: +44 (0)207 1048082, Email: nrescommittee.northeast-newcastleandnorthtyneside2@nhs.net, ref: 19/NE/0019 - approval pending
Health condition(s) or problem(s) studied	Crohn's disease
Intervention	There will be two parts to the planned research involving three hospitals in Birmingham. Part 1 is a vitamin D screening study, where adults will be asked to have a finger-prick blood test to check their vitamin D levels. They will asked to answer dietary and lifestyle questions. Adults found to have vitamin D deficiency in part 1 may be invited to join part 2 of the research. Part 2 is a vitamin D supplementation study where participants will be given a daily vitamin D capsule to take by mouth for 24 weeks. They will be randomly allocated to 2 different groups with each group receiving a different dose of vitamin D. Web randomisation will be carried out. This will be stratified by site in a ratio of 1:1. Arm A: Fultium D3 Daily 400iu, one to be taken daily for 24 weeks Arm B: Fultium D3 3,200iu, one to be taken daily for 12 weeks followed by Fultium D3 800iu one to be taken daily for 12 weeks. There is no control group. Participants will have blood tests at the start,12 weeks and 24 weeks. They will complete quality of life questionnaires at the start and after 24 weeks. The last appointment will be a final follow-up appointment after 36 weeks.
Intervention type	Other
Primary outcome measure(s)	Screening studies: 25(OH) vitamin D results measured using finger-prick blood test to determine prevalence of vitamin D deficiency <50nmol/l during winter and summer months Feasibility trial: Feasibility assessed at the end of the trial when the final participant has had their final follow up appointment: 1. Consent rate 2. Compliance rate 3. Retention rate 4. Completion rates of efficacy outcomes 5. Adverse events The following success criteria will be applied: 1. At least 50% of all eligible patients can be recruited and consented to join the vitamin D supplementation feasibility trial 2. At least 80% participant compliance with the intervention measured by a treatment diary. 3. Retention and follow up in at least 80% of all recruited participants at 6 months 4. Completion of all trial processes in at least 80% of recruited participants. 5. Absence of adverse reactions and causative adverse events in at least 80% of participants. Outcomes will be either: Feasible with no modifications Feasible with modifications Main study not feasible All criteria must be met to deem the study feasible without modifications. At least criteria 1 must be met to deem the study feasible with modifications. If none of the criteria are met then the study is not feasible.
Key secondary outcome measure(s)	Outcomes that will be used to assess efficacy in future definitive trial: Primary outcome: health related quality of life measured using the Inflammatory Bowel Disease Questionnaire (IBDQ) at baseline and 24 weeks
Completion date	31/12/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	300
Total final enrolment	172
Key inclusion criteria	Screening study: 1. Confirmed diagnosis of Crohn's Disease (CD) 2. > = 18 years of age 3. Written informed consent Intervention study: 1. Confirmed diagnosis of CD 2. Identified as having Vitamin D deficiency < 50 nmol/L in the Winter screening study 3. > = 18 years of age 4. Already receiving treatment for CD as per National Institute for Health and Care Excellence (NICE) Guidance or those in remission and not currently receiving treatment but who continue to attend hospital out-patient appointments 5. Written informed consent
Key exclusion criteria	Screening study: Does not meet inclusion criteria Intervention study: 1. Currently taking over the counter vitamin D, fish oil or multi-vitamin supplementation and unwilling to stop this to participate in the intervention study 2. Currently receiving: 2.1. Vitamin D containing supplements prescribed by a healthcare professional 2.2. Bisphosphonates 2.3. Digitalis or other cardiac glycosides 2.4. Phenytoin 2.5. Barbituates (e.g. Amylobarbitone, Butobarbitone, Methyl Phenobarbitone, Pentobarbitone, Quinalbarbitone, Amylobarbitone) 2.6. Actinomycin 2.7. Imidazole 3. With known hyperparathyroidism 4. With known sarcoidosis 5. With known renal disease or kidney stones 6. With known hypercalcaemia (corrected serum calcium > = 2.60 mmol/L) 7. With known underlying liver disease 8. With known hypersensitivity to vitamin D supplements or any of the trial medication excipients 9. Who are pregnant, breastfeeding, trying to conceive or women of child-bearing capacity who decline to have a pregnancy test where applicable and/or decline to take effective contraceptive measures during the intervention period 10. Individuals who have participated in a trial testing a medicinal product within 6 months preceding screening
Date of first enrolment	19/09/2019
Date of final enrolment	31/01/2021

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

University Hospitals Birmingham, Queen Elizabeth Hospital (lead site)

Mindelsohn Way
Edgbaston
Birmingham
B15 2WB
United Kingdom

University Hospitals Birmingham, Birmingham Heartlands Hospital

Bordesley Green East
Birmingham
B9 5SS
United Kingdom

University Hospitals Birmingham, Good Hope Hospital

Rectory Road
Sutton Coldfield
B75 7RS
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to the study being a feasibility study only.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article		20/03/2021	22/03/2021	Yes	No
Basic results			14/04/2023	No	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN15717783_BasicResults.pdf: Basic results

Editorial Notes

14/04/2023: A basic results summary has been uploaded.
13/12/2021: The total final enrolment was added.
22/03/2021: Publication reference added.
08/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/05/2020 to 31/01/2021.
2. The overall trial end date was changed from 31/12/2020 to 31/12/2021.
3. The intention to publish date was changed from 31/10/2021 to 31/10/2022.
17/04/2020: Due to current public health guidance, recruitment for this study has been paused.
19/03/2020: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/03/2019 to 19/09/2019.
2. The recruitment end date was changed from 01/06/2019 to 31/05/2020.
3. The overall end date was changed from 31/10/2020 to 31/12/2020.
20/09/2019: The following changes were made:
1. The ethics approval was updated.
2. The overall trial end date was changed from 01/06/2019 to 31/10/2020.
3. The intention to publish date was changed from 01/06/2020 to 31/10/2021.
22/03/2019: The condition has been changed from "Specialty: Gastroenterology, Primary sub-specialty: Inflammatory Bowel Disease; Health Category: Oral and Gastrointestinal; Disease/Condition: Noninfective enteritis and colitis" to "Crohn's disease" following a request from the NIHR.