Effect of Vitamin D Treatment on Fatigue
Condition: Vitamin D Deficiency
MeSH terms: Vitamin D Deficiency; Fatigue
Study type: Interventional
Phase: Phase 3

Summary: 
      Primary objective

      -Change in Fatigue Assesment Score (FAS) between the first visit (baseline) and 28 (+maximum
      7) days after oral administration of 100 000 E vitamin D (Cholecalciferol).

      Secondary objectives

        -  Effect of oral administration of vitamin D on serum vitamin D levels (25-Hydroxy-Vitamin
           D = Colecalciferol), PTH, Calcium, and Phosphate as compared to placebo.

        -  Efficacy of vitamin D (Colecalciferol) administration on fatigue using the short
           self-developed FCA-Test

        -  Safety of 100 000 E oral vitamin D (Colecalciferol) administration as compared to oral
           placebo. Laboratoty parameters such as serum calzium and phosphate levels and the number
           of adverse events compared to placebo will be used for safety monitoring.

        -  Efficacy of oral administration of vitamin D (Cholecalciferol) on plasma FGF-23,
           Sclerostin and Klotho levels compared to placebo.
    

Detailed description: 
      1. General Design

           This is a randomized, double blind, mono-centric, placebo-controlled interventional
           study of the effects of oral vitamin D supplementation on self-reported fatigue. Overall
           80 patients with proven vitamin D deficiency (20-Hydroxy-Vitamin D ≤ 20 µg/L) who
           fulfill all the eligibility criteria will be randomized and enrolled to receive vitamin
           D or placebo in 1:1 ratio. All patients must sign an informed consent prior to enrolment
           and meet eligibility criteria. All patients will be recruited at the Medical Outpatients
           Department of University Hospital Zürich.

           Screening, Part 1: Consecutive patients consulting the Medical Outpatients Department,
           complaining of fatigue, will be asked to participate in the study. Basic questionnaire
           for fatigue will be applied to confirm fatigue symptoms.

           Screening, Part 2: In positive case, the patients will be asked to sign an informed
           consent. Beck Depression Inventory (BDI), Mini International Neuropsychiatric Interview
           (M.I.N.I.) and Insomnia Severity Index (ISI) will be administered to exclude depression,
           sleep disorders and major psychiatric disorders respectively. Thereafter blood will be
           tested according to table 1. Patients with vitamin D levels below 20 µg/L will undergo
           randomization. Participants will be informed about their results of vitamin D levels by
           the telephone, a treatment appointment within 2 weeks after screening will be arranged
           for participants with vitamin D levels ≤ 20 µg/L.

           Visit A (within 2 weeks after randomisation): Routine clinical examination will be
           performed. Baseline Fatigue assessment scale (FAS) score will be documented, following
           by blood and urine samples according to table 1 to measure the baseline vitamin D-, PTH-
           and Calcium levels. Blood samples will undergo centrifugation. Blood and urine samples
           will be frozen at -80°C.

           Oral Vitamin D preparation or placebo will be administered according to the protocol in
           a double blinded manner. The drug administration will be done by an independent person
           e.g. a physician assistant or study nurse directly observing the drug intake. During the
           administration, procedures are implemented which ensure that the subjects cannot
           distinguish between placebo and verum (identical appearance, taste and smell).

           Visit B ( 4 weeks after Visit A + maximum 7 days): Patients will undergo the same
           Assessment of Fatigue by filling out FAS questionnaire. Additionally, a short
           self-developed test Fatigue course assessment (FCA) will be applied to evaluate
           symptomatic response. Thereafter blood and urine samples will be taken to document
           biochemical response: Vitamin D-, PTH-, phosphate and calcium levels.

           The Vitamin D status of the subjects will be monitored by standard clinical chemical
           parameters. Safety assessments will include pre- and post-treatment measurement of vital
           signs, clinical laboratory assessments, and the recording of adverse clinical events.

        2. Selection of study population / Subject recruitment

           Patients will be informed about the study at a regular medical visit at the medical
           outpatients department USZ. Potential subjects will be provided with the participant
           information sheet and fill in the basic questionnaire for fatigue.

           After informed consent has been obtained, all study-specific information will be
           collected to determine if a patient meets the inclusion criteria without violating any
           of the exclusion criteria. A total number of 80 subjects will be enrolled, with an
           enrolment goal of 12 subjects per month. Recruitment will take place in the medical
           outpatient department (Klinik und Poliklinik für Innere Medizin) of the University
           Hospital in Zurich. If monthly enrolment goals cannot be achieved, announcements will be
           posted on the university's announcement boards and on the internet page of the USZ
           medical department. Patients will receive no financial compensation.

           The specific inclusion and exclusion criteria for enrolling subjects in this study are
           described in the following sections.

        3. Prior and Concomitant Therapy

           According to the inclusion/exclusion criteria (see above), chronic intake of concomitant
           medication is not allowed, except oral contraceptives. Intake of Vitamin D preparations
           during the last 8 weeks before the start of the trial protocol and during the trial is
           not allowed. Vitamin preparations or herbal medicine should be withheld during the study
           period.

           Sporadic medication with e.g. NSAID or paracetamol for symptomatic treatment of
           intercurrent viral infections or occasional headaches is allowed. All concomitant
           medications have to be recorded on the CRF. Subjects taking additional vitamin D
           preparations drugs the study course will be excluded from the study.

        4. Randomization and blinding

           Overview:

           A randomization procedure will be used to avoid a bias in the assignment of the study
           subjects to the two treatment groups (oral vitamin D, oral placebo). Randomization
           lists, preparation of study drugs and placebo, labelling and drug accountability will be
           done by the hospital pharmacy (Kantonsapotheke Zürich). The randomisation list will be
           preserved by the hospital pharmacy. The oral intake will be directly observed by a
           physician assistant or study nurse. As placebo and verum are manufactured having
           identical appearance, taste and smell, study participants can not differ between placebo
           and verum.

           Procedure:

           Patients will be assigned to treatment groups based on a randomization list/schedule
           prepared by the hospital pharmacy prior to the trial. Patients will receive a
           randomization number. Randomized patients who terminate their study participation for
           any reason regardless whether the study medication was taken or not, will retain their
           randomization number. The next patient will be given the next randomization number.

           An Emergency Code Break preserved in a sealed Emergency Code Envelope will be available
           to the investigator. This envelope with the Code Break should only be opened in
           emergency situations when the identity of the investigational product must be known by
           the investigator in order to provide appropriate medical treatment.

        5. Treatment / Dosage and administration

      The patients will be randomized to one of the 2 treatment groups (40 participants in each
      group): Group I: oral vitamin D; Group II: oral placebo.

        -  Group I (oral vitamin D): 100 000 E Vitamin D (Colecalciferol) will be applied as a
           single dose as two capsules containing 50 000 E each.

        -  Group II (oral placebo): 2 placebo capsules will be applied as a single dose The drug
           preparations will be delivered and labelled by the hospital pharmacy according to
           standard operating procedures and GMP guidelines.

      After the study finalisation, the placebo group will be offered a treatment with Vitamin D.

      5. Study drug information Vitamin D used in this study is 2 capsules containing 50 000 E
      Cholecalciferol each, prepared by the university hospital pharmacy.

      Placebo will be prepared by the university hospital pharmacy in a capsule of identical
      appearance, taste and smell.

      6. Packing and Labeling Study medication (oral Vitamin D and placebo) will be provided by the
      hospital pharmacy, labelled and packaged according to Swiss guidelines and EU-GMP guidelines.
    

Intervention name(s): Vitamin D; placebo
Intervention type(s): Drug; Other
Intervention description(s): 100 000 units oral vitamin D as 2 capsules 50 000 units each; 2 placebo capsules will be applied as a single dose
Other intervention name(s): Cholecalciferol
Intervention MeSH terms: Vitamin D; Cholecalciferol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: vitamin D; fatigue