Timed Release Tablet Prednisone in Polymyalgia Rheumatica

Circadian Variation in Cytokines and the Effect of Timed Release Tablet Prednisone in Polymyalgia Rheumatica

Polymyalgia Rheumatica (PMR) is a disease that usually affects older people. Patients complain of stiffness and pain around the shoulders and hips. The stiffness is more severe in the morning.

Research in Rheumatoid Arthritis (RA), which is also much worse in the mornings, has shown that IL-6 (a chemical messenger) peaks in the morning with very low levels in the evening. This may explain why stiffness is most severe in the morning. The investigators have recently shown that timed release tablet (TRT) prednisone reduced morning IL-6 levels close to normal in RA patients.

In PMR, IL-6 levels are high. Given that both RA and PMR have the same variation of symptoms (worse in the morning); it's likely that PMR patients have the same variation in IL-6 levels. In a pilot study of 4 patients conducted within our department, IL-6 levels did, indeed, show a pattern similar to that found in RA patients, but the number of patients is small and the results need to be confirmed.

PMR is treated with moderate doses of glucocorticoid for about 2 years. While generally abolishing symptoms, these doses are very likely to cause adverse effects such as high blood pressure, weight gain and diabetes. These side effects are much less frequent when lower doses are used but these are not sufficient to control PMR using traditional dosing regimes.

Therefore, the investigators wish to investigate whether TRT prednisone in PMR will reduce IL-6 and morning symptoms similar to those in RA. The investigators think that it will do so, and will achieve symptomatic relief at a lower dose. If this is the case, then treating patients with lower doses may mean reduced risk of glucocorticoid induced side effects in the future.

Patients will be recruited through the outpatient clinics at the University Hospitals Bristol, NHS Foundation Trust, Rheumatology Centre. Each patient will give fully informed consent after being given details of the study and a patient information sheet. The research doctor will take the consent 2-5 days after this information has been provided and with the presence of a witness. The study will consist of the collection and analysis of sequential blood samples over a 24 hour period on 2 occasions 2 weeks apart, taking TRT prednisone 7 mg / standard release prednisolone 7 mg for the intervening period. The investigators will aim to recruit 12 patients in each arm. A single blood sample will be taken when the patient comes for a routine review 2 weeks later.

Study Overview

• Status: Completed
• Conditions: Polymyalgia Rheumatica
• Intervention / Treatment: Drug: Timed Release Tablet Prednisone; Drug: Prednisolone

Detailed Description

The volunteers will stay overnight in the Rheumatology Centre; 24-hour Research Facility on two occasions (Night A and Night B) 12-16 days apart. This slight flexibility will allow some leeway in arranging residency nights. In general the investigators will aim for 14 days. After Night A, each volunteer will be randomized (in pre-prepared sealed envelopes) to take one tablet morning or evening. Half the patients will take active standard release prednisolone in the morning. The other half will receive active TRT Prednisone 7mg to be taken each evening at 22:00 until the day after Night B. All study medication will then be discontinued and standard therapy (prednisolone 15mg each morning) commenced. Patients will be reviewed after 2 weeks to ensure expected clinical response and to measure IL-6 and other cytokines in the blood sample that is also needed to check the acute phase response.

On Night A and Night B, volunteers will attend the Rheumatology Centre at 15:00.

First, standard assessment tools will be used by the research doctor to assess the state of the patient's condition.

These assessments will be:

• Morning stiffness (minutes)
• Pain (visual analogue scale)
• Patient's opinion of condition
• Clinician's opinion of condition
• Health Assessment Questionnaire
• BRAF-MDQ fatigue scale and the Hospital Anxiety and Depression Scale.

An intravenous (IV) cannula will be inserted into the elbow area. At least one hour after the IV cannula is placed, but usually at 16:30, a blood sample (2ml) will be taken through the IV cannula and the cannula flushed. At 22:30 the main lights will be switched off and the volunteer encouraged to sleep. In total, 20 samples will be taken from the cannula over 24 hours.

The investigators will calculate mean and standard deviation (or non-parametric analysis if the data are not normally distributed) for blood cytokines for each time point. These mean and standard deviations will be compared for pre- and post-TRT prednisone samples.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Avon
    • Bristol, Avon, United Kingdom, BS2 8HW
      • University Hospitals Bristol NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of PMR by standard criteria. The Bird criteria will be used. 3 or more features are required to make the diagnosis.

  • Bilateral shoulder pain/stiffness
  • Duration of symptoms <2/52
  • Initial ESR >40 mm/h
  • Stiffness >1 h
  • Age >65 years
  • Depression and/or weight loss
  • Bilateral upper arm tenderness
• Are over 50 but less than 85 years old.
• No or stable NSAID or analgesic therapy for at least 7 days.
• Currently active disease defined by a CRP at least 10mg/L, ESR at least 29mm in one hour or PV >1.72

Exclusion Criteria:

• Currently on oral glucocorticoid treatment or taken within 2 months
• Parenteral glucocorticoid treatment with the last 2 months
• Pregnancy and lactation
• Inflammatory diseases such as inflammatory bowel disease, colitis, asthma
• Co-existent giant cell arteritis
• Other auto-immune diseases
• Cancer
• Infections, treatment with antibiotics within the past 6 weeks
• Significant renal disease (creatinine >150 μmol/L)
• Significant hepatic impairment
• Participation in a clinical trial within the past 30 days
• Working shift employee
• Jet lag

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Timed Release Tablet Prednisone; 12 patients will be taking the intervention night time timed release tablet (TRT) prednisone at a dose of 7mg a day over 2 weeks.	Drug: Timed Release Tablet Prednisone; Dose: 7mg, taken at 10pm every night for 2 weeks in the form of oral tablets.; Other Names: Lodotra
ACTIVE_COMPARATOR: Standard Prednisolone; 12 patients will be taking morning Prednisolone at a dose of 7mg over 2 weeks.	Drug: Prednisolone; Dose: 7mg, taken in the morning for 2 weeks in the form of oral tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Peak Serum IL-6 Concentration	Pre-treatment (Night A) peak minus post-treatment (Night B) peak. Peaks defined as the highest value for each patient from measures at 0, 1.5, 3, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5, 10.5, 11.5, 12.5, 13.5, 14.5, 15.5, 17, 19, 20.5, 22, and 24 hours after 16.30 on day before treatment (Night A) and last day of treatment (Night B) and the peak identified for each one.	24 hours
Change in Area Under the Curve (AUC) of Plasma IL-6	Pre-treatment (Night A) AUC minus post-treatment (Night B) AUC. AUC calculated from measures at 0, 1.5, 3, 4.5, 5.5, 6.5, 7.5, 8.5, 9.5, 10.5, 11.5, 12.5, 13.5, 14.5, 15.5, 17, 19, 20.5, 22, and 24 hours after 16.30 on day before treatment (Night A) and last day of treatment (Night B).	24 hour measurements 2 weeks apart

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Morning Stiffness	How long was your morning stiffness today? Pre-treatment (Night A) value minus post-treatment (Night B) value divided by pre-treatment value.	2 weeks
Pain (Severity)	100mm visual analogue scale. Question: How much pain have you had in the last 24 hours? Anchors: No pain; Severe pain. Min score 0, Max score 100. Higher value is worse outcome.	24 hour period after 2 weeks of treatment
Patient's Opinion of Condition	100mm visual analogue scale. Question: Considering all the ways your pain and/or stiffness affect(s) you, please mark on the line how well you are doing. Anchors: Very well; Very badly. Min 0 Max 100 (poor outcome).	Current value at baseline and after 2 weeks treatment
Clinician's Opinion of Disease Activity.	100mm visual analogue scale. Question: Clinician's opinion of disease activity. Anchors: None; Severe Min 0 Max 100 (worse)	Current at baseline and after 2 weeks treatment

Collaborators and Investigators

• Sponsor: University Hospitals Bristol and Weston NHS Foundation Trust
• Investigators: Principal Investigator: John R Kirwan, MBBS,MD,FRCP, University Hospitals Bristol and Weston NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (ACTUAL): November 1, 2010
• Study Completion (ACTUAL): March 1, 2011

Study Registration Dates

• First Submitted: February 2, 2009
• First Submitted That Met QC Criteria: February 2, 2009
• First Posted (ESTIMATE): February 4, 2009

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Circadian variations of cytokines in PMR; effect of TRT Prednisone in cytokines
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Muscular Diseases; Vasculitis; Skin Diseases, Vascular; Vasculitis, Central Nervous System; Arteritis; Polymyalgia Rheumatica; Giant Cell Arteritis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone; Prednisone
• Other Study ID Numbers: ME/2008/3031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO