Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project (TOFAT)

• ClinicalTrials.gov Identifier: NCT04175886
• Recruitment Status: Recruiting
• First Posted: November 25, 2019
• Last Update Posted: June 25, 2020
• Sponsor: University Hospital, Lille
• Collaborator: Pfizer
• Information provided by (Responsible Party): University Hospital, Lille

Study Description

Brief Summary:

Inflammatory rheumatic diseases (IRD), such as rheumatoid arthritis, are characterized by adverse changes in body composition. Lean mass and bone mineral density are usually reduced while adiposity (total fat mass, visceral adiposity…) is increased in comparison with healthy controls. Many factors may influence the body composition of those patients such as aging, Disease Modifying Anti-Rheumatic Drugs (DMARDs), nutrition and physical activity.

However, data on body composition and adverse changes under DMARDs in patients with rheumatoid arthritis (RA) are actually scarce. This is the case with tofacitinib (targeted synthetic DMARD or tsDMARD) while preliminary data let us think that this treatment may influence body composition and bone mineral density.

This study is going to be the first to focus on changes in body composition (fat mass and lean mass), bone mineral density and bone marrow adiposity under tofacitinib.

Condition or disease	Intervention/treatment
Rheumatoid Arthritis	Drug: Tofacitinib

Study Design

• Study Type: Observational
• Estimated Enrollment: 72 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project
• Actual Study Start Date: February 25, 2020
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Patients with rheumatoid arthritis; Patients with rheumatoid arthritis with an indication for tofacitinib: 5mgx2 per day	Drug: Tofacitinib; Patients will be treated with tofacitinib
Healthy subjects; Healthy subjects matched to cases (1:1) on age (±5 years), sex, and menopausal status for women and body mass index (BMI, ±3 kg/m²)

Outcome Measures

Primary Outcome Measures :

1. Variation in visceral adiposity (VAT or Visceral Adipose Tissue) in cm² [ Time Frame: Between the measurement before and after 6 months of tofacitinib treatment (difference before/after). ]
   Variation in visceral adiposity (VAT or Visceral Adipose Tissue) in cm²

Secondary Outcome Measures :

1. Measurements of VAT in cm². [ Time Frame: at baseline ]
   Measurements of VAT in cm²
2. Measurements of total fat mass (TBF) in kg, total lean mass (TLM) in kg, appendicular lean mass (aLM) in kg [ Time Frame: at baseline ]
   Measurements of total fat mass (TBF) in kg, total lean mass (TLM) in kg, appendicular lean mass (aLM) in kg
3. Measurements of body fat percentage (%) [ Time Frame: at baseline ]
   Measurements of body fat percentage (%)
4. Measurements of fat mass index (FMI) in kg/m² and skeletal muscle mass index (SMI) in kg/m² [ Time Frame: at baseline ]
   Measurements of fat mass index (FMI) in kg/m² and skeletal muscle mass index (SMI) in kg/m²
5. Measurements of Bone mineral Density (BMD) in g/cm². [ Time Frame: at baseline ]
   Measurements of Bone mineral Density (BMD) in g/cm².
6. Change in body fat percentage (% between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
   Change in body fat percentage (%) between measurement
7. Change in total fat mass (TBF) between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
   Change in total fat mass (TBF) in kg between measurement
8. Change in fat mass index (FMI) in kg/m², between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
   Change in fat mass index (FMI) in kg/m², between measurement
9. Change in total lean mass (TLM, kg) and appendicular lean mass (aLM) in kg between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
   Change in total lean mass (TLM, kg) and appendicular lean mass (aLM) in kg between measurement
10. Change in skeletal muscle mass index (SMI) in kg/m² between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
    Change in skeletal muscle mass index (SMI) in kg/m² between measurement
11. Change in BMD (in g/cm²) at the lumbar spine (L1-L4) and non-dominant total hip between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment (difference before/after). ]
    Change in BMD (in g/cm²) at the lumbar spine (L1-L4) and non-dominant total hip between measurement
12. Variation of bone remodelling markers (Cross-laps (CTX) and Type I procollagen N-terminal propeptide (P1NP)) between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment. ]
    Variation of bone remodelling markers (Cross-laps (CTX) and Type I procollagen N-terminal propeptide (P1NP)) between measurement
13. Variation in leptin (ng/ml) between measurement. [ Time Frame: Before and after 6 months of tofacitinib treatment ]
    Variation in leptin (ng/ml) between measurement.
14. Change in bone marrow adiposity (%) at the lumbar spine between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment. ]
    Change in bone marrow adiposity (%) at the lumbar spine between measurement
15. Variation in Short Physical Performance Battery Protocol (SPPB) between measurement [ Time Frame: Before and after 6 months of tofacitinib treatment. ]
    Variation in Short Physical Performance Battery Protocol (SPPB) between measurement
16. Changes in the parameters of the primary outcome and the secondary outcomes (n°2 to 8) [ Time Frame: Before and after 12 months of tofacitinib treatment. ]
    Changes in the parameters of the primary outcome and the secondary outcomes (n°2 to 8)

Biospecimen Retention:   Samples Without DNA

Whole blood, serum

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

The study population is composed of adult patients with moderately to severely active RA for whom tofacitinib is indicated and who are followed in the department of rheumatology at Lille University Hospital

Criteria

Inclusion Criteria:

• Adult patient's ≥18 years old with moderately to severely active Rheumatoid Arthritis (RA) (ACR/EULAR criteria )
• Previously untreated with Janus Kinase (JAK) inhibitors
• With an indication for tofacitinib will be eligible.
• All patients will have to be treated with tofacitinib either alone or with methotrexate. -Healthy volunteers should be ≥18 years old.

Exclusion Criteria:

• • treatment with more than three anti-Tumor Necrosis Factor alpha (TNFα). Patients who were receiving anti-TNFα will be required a washout period lasting at least five-half-lives before to start tofacitinib,

  • previously exposed to JAK inhibitors,
  • patients who were receiving non-anti-TNFα biologics (abatacept, tocilizumab, sarilumab or rituximab) will be required a washout period lasting at least five-half-lives before to start tofacitinib
  • Concomitant methotrexate (MTX) will be permitted if started ≥3 months prior to study start and at a stable dose (≤25 mg/week) for ≥4 weeks.
  • history or discovery of an osteoporotic fracture AND/OR T-score≤-3 if ≥50 years AND/OR Z-score ≤-3 if <50 years during the screening phase,
  • current treatment with oral corticosteroids higher than 10 mg prednisone/day,
  • pathologies or treatments that could affect the bone metabolism (breast cancer with aromatase inhibitors, gastrointestinal malabsorption, stomach cancer, primary hyperparathyroidism, uncontrolled hyperthyroidism…),
  • weight> 160 kg,
  • patients on restrictive diets or considering such a diet during the study period,
  • patients with an intense exercise program or planning to benefit from it during the study period,

Contacts and Locations

Contacts

Contact: Jean-Guillaume Letarouilly, MD; 0320445962 ext +33; jg.letarouilly@chru-lille.fr

Locations

France

Lille University Hospital; Recruiting

Lille, France

Contact: Jean-Guillaume Letarouilly, DR +33320446926 jeanguillaume.letarouilly@chru-lille.fr

Contact: Julien Paccou, PR +33320446926 julien.paccou@chru-lille.fr

Sponsors and Collaborators

University Hospital, Lille

Pfizer

Investigators

• Principal Investigator: Jean-Guillaume Letarouilly, MD; University Hospital, Lille

More Information

Publications of Results:

Book C, Karlsson MK, Akesson K, Jacobsson LT. Early rheumatoid arthritis and body composition. Rheumatology (Oxford). 2009 Sep;48(9):1128-32. doi: 10.1093/rheumatology/kep165. Epub 2009 Jul 13.

Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum. 2000 Mar;43(3):522-30.

Toussirot É, Mourot L, Dehecq B, Wendling D, Grandclément É, Dumoulin G; CBT-506. TNFα blockade for inflammatory rheumatic diseases is associated with a significant gain in android fat mass and has varying effects on adipokines: a 2-year prospective study. Eur J Nutr. 2014 Apr;53(3):951-61. doi: 10.1007/s00394-013-0599-2. Epub 2013 Oct 31.

Marouen S, Barnetche T, Combe B, Morel J, Daïen CI. TNF inhibitors increase fat mass in inflammatory rheumatic disease: a systematic review with meta-analysis. Clin Exp Rheumatol. 2017 Mar-Apr;35(2):337-343. Epub 2016 Dec 13. Review.

Engvall IL, Tengstrand B, Brismar K, Hafström I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. Arthritis Res Ther. 2010;12(5):R197. doi: 10.1186/ar3169. Epub 2010 Oct 21.

Tournadre A, Pereira B, Dutheil F, Giraud C, Courteix D, Sapin V, Frayssac T, Mathieu S, Malochet-Guinamand S, Soubrier M. Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J Cachexia Sarcopenia Muscle. 2017 Aug;8(4):639-646. doi: 10.1002/jcsm.12189. Epub 2017 Mar 18.

Other Publications:

Dodington DW, Desai HR, Woo M. JAK/STAT - Emerging Players in Metabolism. Trends Endocrinol Metab. 2018 Jan;29(1):55-65. doi: 10.1016/j.tem.2017.11.001. Epub 2017 Nov 27. Review.

Fleischmann RM, Huizinga TW, Kavanaugh AF, Wilkinson B, Kwok K, DeMasi R, van Vollenhoven RF. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis. RMD Open. 2016 Jul 26;2(2):e000262. doi: 10.1136/rmdopen-2016-000262. eCollection 2016.

Tatsumi Y, Nakao YM, Masuda I, Higashiyama A, Takegami M, Nishimura K, Watanabe M, Ohkubo T, Okamura T, Miyamoto Y. Risk for metabolic diseases in normal weight individuals with visceral fat accumulation: a cross-sectional study in Japan. BMJ Open. 2017 Jan 16;7(1):e013831. doi: 10.1136/bmjopen-2016-013831.

• Responsible Party: University Hospital, Lille
• ClinicalTrials.gov Identifier: NCT04175886
• Other Study ID Numbers: 2018_38; 2019-001159-37 ( EudraCT Number )
• First Posted: November 25, 2019
• Last Update Posted: June 25, 2020
• Last Verified: June 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Lille:

rheumatoid arthritis; tofacitinib; body composition; bone marrow adiposity; bone marrow density

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Obesity; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Tofacitinib; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action