Spondylitis Trial of Apremilast for Better Rheumatic Therapy (START)

Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004)in the Treatment of Ankylosing Spondylitis (AS)

This study will evaluate the effectiveness of apremilast in AS as measured by improvement in patients' signs and symptoms of the disease and changes in imaging. Additionally the safety and tolerability of apremilast in AS will be assessed.

Study Overview

• Status: Completed
• Conditions: Ankylosing Spondylitis
• Intervention / Treatment: Drug: Placebo (sugar pill); Drug: Apremilast

Detailed Description

Presently, there are very few treatments available which affect the progression of the disease in the spine. The only proven treatment is the use of drugs inhibiting tumour necrosis factor alpha (TNF). However, there are limitations with this treatment in that it needs to be administered via an injection and is also very expensive. Therefore it is necessary to develop new therapeutic agents for this condition.

Apremilast (the study drug) is an oral tablet which has been shown to inhibit TNF production in a mouse model of inflammation. It has also been used in clinical trials for asthma and psoriasis in humans with good affect and tolerability.

These studies were funded by Celgene Corporation and they will be funding this study.

The patients will be recruited from hospitals by Consultant referral. The patients will have had AS for at least 2 years and their symptoms will have been uncontrolled on conventional non-steroidal anti-inflammatory drugs such as ibuprofen. Patients will be randomised to either receive apremilast or a placebo and treated over a period of 12 weeks. They will then be followed up for 28 days after the treatment period.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W6 8RF
    • The Kennedy Institute Clinical Trials Unit, 4 West, Charing Cross Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent to participate in this trial

• Diagnosis of ankylosing spondylitis as defined by the modified New York criteria (1984) as follows:

  1. a history of inflammatory back pain;
  2. limitation of motion of the lumbar spine in both the sagittal and frontal planes;
  3. limited chest expansion, relative to standard values for age and sex;
  4. definite radiographic / imaging evidence of sacroiliitis and/or spinal inflammation
• Patients must have daily spinal pain and stiffness for at least 2 weeks prior to randomization. This is defined by having a score of >1 on questions #2 and #5 of the BASDAI score for the 2 weeks prior to randomization.
• Patients receiving NSAIDS and/or COX-2 inhibitors must be on stable doses for at least 2 weeks prior to randomization.
• Age >18 years
• Male and female patients, who are not surgically sterile or postmenopausal, must use reliable methods of birth control for the duration of the study. Males must agree to use barrier contraception for 3 months following the end of the trial.
• Women of childbearing potential, not surgically sterile or postmenopausal, must have a negative serum beta HCG.

Exclusion Criteria:

• Use of DMARDs (methotrexate, d-penicillamine, sulfasalazine, azathioprine, hydroxychloroquine, or gold) within 8 weeks of randomization.
• Use of systemic corticosteroids within 4 weeks of randomization
• Use of intravenous or intra-articular corticosteroids within 4 weeks of randomization
• Use of TNF alpha blockers (eg, infliximab, adalimumab) or etanercept as follows:

Compound PK Exclusion period Etanercept T ½ = 102 hrs = 4.25 days 4 weeks Adalimumab T ½ 2 wks; 5 half lives 10 weeks 10 weeks Infliximab T ½ 7.7-9.5 d 12 weeks 8 weeks after maintenance dose median infx conc 0.5-6 mcg/ml

• Therapy with an investigational agent within 30 days of randomization or 5 half-lives (pharmacokinetic or pharmacodynamic), which ever is longer
• Known HIV or hepatitis B or C infection

• Exclusion of tuberculosis (TB)

  • History of active Mycobacterium tuberculosis infection (any subspecies) within 3 years prior to the screening visit. Infections that occurred > 3 years prior to entry must have been effectively treated.
  • History of incompletely treated latent Mycobacterium tuberculosis infection (as indicated by a positive Purified Protein Derivative [PPD] skin test)
  • Clinically significant abnormality on chest x-ray (CXR) if mantoux >5mm or ELISPOT positive
• History of other rheumatic autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, etc.)
• Pregnant or nursing women
• Any condition, in the investigator's opinion, which places the patient at an undue risk by participating in the study.
• Contraindication to MRI and other MRI exclusions following local centre guidelines (Appendix H)
• An estimated glomerular filtration rate (eGFR) of < 60 ml/min (because of the small risk of nephrogenic sclerosing fibrosis with gadolinium intravenous contrast), if patient is to have MRI with gadolinium contrast .
• Claustrophobia
• Hemoglobin < 9 g/dL
• White blood cell (WBC) count < 3000 /μL (≥ 3.0 X 109/L) and ≥ 14,000/μL (≥ 20 X 109/L)
• Neutrophils < 1500 /μL (< 1.5 X 109/L)
• Platelets < 100,000 /μL (< 100 X 109/L)
• Serum creatinine > 1.5 mg/dL (> 132.6 μmol/L)
• Total bilirubin > 2.0 mg/dL
• Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]) > 1.5x upper limit of normal (ULN)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; placebo twice a day for 12 weeks, 4 weeks follow up	Drug: Placebo (sugar pill); twice a day
ACTIVE_COMPARATOR: Apremilast; 30 mg twice a day for 12 weeks, 4 weeks follow up	Drug: Apremilast; 10mg twice a day, dose was titrated by 20mg every 2 days until the maximum dose 30mg twice a day for 12weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Apremilast in Patients With AS, Changes in BASDAI Score From Baseline	Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 0 - 10 score, higher reduction in the scores suggest better suboptimal control of disease.	Baseline and 12 weeks
Changes of Apremilast on the Signs and Symptoms of AS, Night Pain From Baseline	This endpoint the night time pain score change was recorded by questionnaire to evaluate the Apremilast effect on symptom, higher reduction better improvement. scale is 0-10	Baseline and 12 weeks
Effect of Apremilast in Patients With AS, Changes in BASFI Score	Bath Ankylosing Spondylitis Functional Index (BASFI), 0 - 10 score, higher reduction in the scores suggest better suboptimal control of disease.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Safety and Tolerability of Apremilast in AS, Number of Participants With Adverse Events	To evaluate the safety and tolerability of Apremilast in AS, the investigator recorded the incidence of adverse events.	16 weeks

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Peter Taylor, Imperial College London

Publications and helpful links

General Publications

• Pathan E, Abraham S, Van Rossen E, Withrington R, Keat A, Charles PJ, Paterson E, Chowdhury M, McClinton C, Taylor PC. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. Ann Rheum Dis. 2013 Sep 1;72(9):1475-80. doi: 10.1136/annrheumdis-2012-201915. Epub 2012 Sep 14.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2009
• Primary Completion (ACTUAL): January 1, 2011
• Study Completion (ACTUAL): January 1, 2011

Study Registration Dates

• First Submitted: July 20, 2009
• First Submitted That Met QC Criteria: July 22, 2009
• First Posted (ESTIMATE): July 23, 2009

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2019
• Last Update Submitted That Met QC Criteria: November 18, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Imaging; Ankylosing spondylitis
• Additional Relevant MeSH Terms: Infections; Joint Diseases; Musculoskeletal Diseases; Arthritis; Spinal Diseases; Bone Diseases; Spondylarthropathies; Bone Diseases, Infectious; Ankylosis; Spondylitis; Spondylarthritis; Spondylitis, Ankylosing; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 4 Inhibitors; Apremilast
• Other Study ID Numbers: 112008; 2008-004229-40 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No