Clinical trial NCT04175886: Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project
Official title: Effects of Tofacitinib on Body Composition, Bone Mineral Density and Bone Marrow Adiposity in Patients With Rheumatoid Arthritis: the TOFAT Project
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis
tofacitinib
body composition
bone marrow adiposity
bone marrow density
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2019-11-25
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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

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.


Eligibility 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,

Primary outcomes:
measure: Variation in visceral adiposity (VAT or Visceral Adipose Tissue) in cm²
timeFrame: Between the measurement before and after 6 months of tofacitinib treatment (difference before/after).
Secondary outcomes:
measure: Measurements of VAT in cm².
timeFrame: at baseline
measure: Measurements of total fat mass (TBF) in kg, total lean mass (TLM) in kg, appendicular lean mass (aLM) in kg
timeFrame: at baseline
measure: Measurements of body fat percentage (%)
timeFrame: at baseline
measure: Measurements of fat mass index (FMI) in kg/m² and skeletal muscle mass index (SMI) in kg/m²
timeFrame: at baseline
measure: Measurements of Bone mineral Density (BMD) in g/cm².
timeFrame: at baseline
measure: Change in body fat percentage (% between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Change in total fat mass (TBF) between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Change in fat mass index (FMI) in kg/m², between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Change in total lean mass (TLM, kg) and appendicular lean mass (aLM) in kg between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Change in skeletal muscle mass index (SMI) in kg/m² between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Change in BMD (in g/cm²) at the lumbar spine (L1-L4) and non-dominant total hip between measurement
timeFrame: Before and after 6 months of tofacitinib treatment (difference before/after).
measure: Variation of bone remodelling markers (Cross-laps (CTX) and Type I procollagen N-terminal propeptide (P1NP)) between measurement
timeFrame: Before and after 6 months of tofacitinib treatment.
measure: Variation in leptin (ng/ml) between measurement.
timeFrame: Before and after 6 months of tofacitinib treatment
measure: Change in bone marrow adiposity (%) at the lumbar spine between measurement
timeFrame: Before and after 6 months of tofacitinib treatment.
measure: Variation in Short Physical Performance Battery Protocol (SPPB) between measurement
timeFrame: Before and after 6 months of tofacitinib treatment.
measure: Changes in the parameters of the primary outcome and the secondary outcomes (n°2 to 8)
timeFrame: Before and after 12 months of tofacitinib treatment.
Other outcomes:
Locations:
city: Lille
country: France
facility: Lille University Hospital
Study officials:
affiliation: University Hospital, Lille
name: Jean-Guillaume Letarouilly, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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. doi: 10.1002/1529-0131(200003)43:33.0.CO;2-Y.
citation: Toussirot E, Mourot L, Dehecq B, Wendling D, Grandclement E, Dumoulin G; CBT-506. TNFalpha 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.
citation: Marouen S, Barnetche T, Combe B, Morel J, Daien 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.
citation: Engvall IL, Tengstrand B, Brismar K, Hafstrom 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.
citation: 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.
citation: Letarouilly JG, Paccou J, Badr S, Chauveau C, Broux O, Clabaut A. Stimulatory Effect of Tofacitinib on Bone Marrow Adipocytes Differentiation. Front Endocrinol (Lausanne). 2022 Jul 6;13:881699. doi: 10.3389/fendo.2022.881699. eCollection 2022.