Teriparatide for Joint Erosions in Rheumatoid Arthritis: The TERA Trial

Rheumatoid Arthritis Clinical Trial

— TERA  

Official title:

Teriparatide for Joint Erosions in Rheumatoid Arthritis: The TERA Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01400516
• Other study ID #: 2010P002691
• Status: Active, not recruiting
• Phase: Phase 4
• First received: July 21, 2011
• Last updated: June 29, 2016
• Start date: August 2011
• Est. completion date: September 2016

Study information

• Verified date: June 2016
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Summary:

The investigators propose a randomized controlled open label study of teriparatide in men or women with rheumatoid arthritis and joint erosions. Specifically, the investigators will examine whether teriparatide in combination with a biologic can retard the development of joint erosions. The study will be conducted at Brigham and Women's Hospital Arthritis Center, several Brigham and Women's Hospital Arthritis Center satellite practices, the University of Massachusetts Medical Center, and Massachusetts General Hospital.

Hypothesis:

The investigators hypothesize that the combination of teriparatide with biologic will be much more effective at retarding erosion progression then a biologic alone.

Description:

I. Introduction:

While generalized osteoporosis causes tremendous disability in patients with RA and occurs relatively frequently in such patients, there has been little research on treatments for osteoporosis in patients with RA. Not only are there important questions about the effects of teriparatide on BMD in patients with RA, but little is known about how it might affect localized bone erosions or RA disease activity.

Recent data in a mouse model of RA suggest that intermittent PTH in the setting of potent immunosuppressives may indeed heal bone erosions. This study showed an additive effect of PTH in addition to a biologic on erosion healing. To the best of our knowledge, this has yet to be demonstrated in humans. That is the primary aim of the proposed study.

II. Objectives and Hypotheses:

To assess the effects of teriparatide among a group of patients with RA and erosions, all using biologics, with respect to:

1. Joint erosion volume by 3D CT scan;

2. Lumbar BMD by DXA;

3. Hip BMD by DXA; and

4. RA disease activity measured by the Disease Activity Score (DAS) and acute phase reactants.

The hypotheses to be tested include:

1. Joint erosion scores, measured by 3D CT scan, will be significantly improved at study completion in patients taking teriparatide.

2. Teriparatide will significantly increase BMD at all sites as measured by DXA.

3. RA disease activity measures will be stable during the study year.

III. Statistical Analyses:

The total erosion volume will be calculated for each hand/wrist and for each of the six sub-regions: radius, ulna, proximal carpals (scaphoid, lunate, triquetrum, and pisiform), distal carpals (capitate, hamate, trapezium, trapezoid, and the CMC joints), MCP joints, and PIP joints. We will perform the hand level-analysis with the individual hands as our study units. In a pre-trial study, repositioning reproducibility was excellent at the hand-level (N = 10) as noted in Duryea et al (REF ). The average total erosion volume in a single hand/wrist was 428.1 mm3. Average erosion volume was smallest at the ulna (6.4 mm3) and largest in the distal carpals (144.8mm3). The intra-class correlation (ICC) values were excellent, ranging from 0.97 to 1.00. The root mean square stand deviation (RMSSD) was 31.2mm3 with a coefficient of variation (CoV) of 7.3%. The CoVs for the six measured hand regions ranged from 7.6% to 21.0%. Individual regions with increased erosion volume tended to have correspondingly larger RMSSD values, while the dependence of the CoV on the total volume was less pronounced.

The outcome for the primary analysis will compare the changes in erosion volume from baseline to follow-up for the subjects receiving teriparatide versus those not. If we find that the change in whole hand erosion volume is significantly better for teriparatide users than controls, then we will have met the primary outcome. In a secondary analysis, we will assess the change in erosion volume at each of the six anatomic sites. As these are secondary analyses, no correction for multiple testing will be pursued. Significance at the whole hand and anatomic site level will be based on a two-tail test of significance with a p-value < 0.05 considered statistically significant.

For all analyses, we will analyze the data at the level of the hand, adjusting for within subject correlation between the two hands using a generalized linear mixed model (GLMM). Baseline subject characteristics will be compared between the two groups using two sample t tests, Chi-square tests or non-parametric tests when applicable. Characteristics of interest include age, gender, duration of RA, serologic status (RF positive and ACPA positive), use of oral corticosteroids, use of concomitant non-biologic DMARDs, baseline DAS score, baseline Total Sharp Score, and baseline HAQ score. If any of these characteristics are found to be imbalanced across groups (p-value < 0.10), those variables will be introduced as possible covariates in the model. However, for this small study with 48 hands, the final model will include no more than 5 predictors.

Several exploratory subgroup analyses will be pursued. These include subgroups of patients based on/with:

• Corticosteroid users or not at baseline;

• Less than or greater than 2 years of RA at baseline;

• In RA remission, defined in three ways: as DAS28 ≤ 2.6, SDAI ≤ 3.3, and boolean (SJC, TJC, patient global and CRP ≤ 1);

• hsCRP < 3mg/L versus ≥ 3mg/L;

• Less than median # of erosions (based on Sharp Score) versus greater than;

• Less than median erosion volume at baseline versus greater than; and

• Depth of erosion: 25% deepest erosions versus other erosions.

The secondary analyses will all be considered exploratory and will follow the same analytic strategy as the primary analyses. Due to small sizes, unadjusted GLMM model will be used in sub-group analyses.

Analyses of secondary outcomes noted above will also be considered exploratory. They will also follow the same analytic strategy as the primary analyses.

If follow up is less than complete, we will estimate the effect under intention-to-treat. Several missing value techniques will be applied to impute the missing outcomes including last observation carried forward, single imputation (e.g. replacing missing values with the sample mean or median), and multiple imputation. Sensitivity analysis will compare these methods with complete case analysis.

IV. Sample Size Estimates:

We have used the estimates derived from the pre-trial replication study to estimate sample size for the trial. We considered analyses both at the level of the subject and at the level of the individual hand. Assessing individual hands provides twice as many observations (two hands for each patient), but these observations are not independent of one another. In our pilot analysis that evaluated 5 patients (10 hands), log-transformation was applied to total volumes to achieve an approximately normal distribution. The average value of log-transformed total volume was 5.32, with standard deviation of 1.34. Assuming that a reasonable ICC between two hands/wrists, on the same patient ranges from 0.20 to 0.50, we estimated the sample size required to achieve 80% power, given a range of differences with a significance level of 0.050 using a two-sided test (see Table 2) 17. To detect a moderate difference of 15%-25% between groups, the sample size needed to achieve adequate statistical power would range from 10 to 34 per study group.

We recruited 12 patients per group (24 hands), assuming an ICC of 0.5.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: September 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years and older

Eligibility

Inclusion Criteria:

All men and women 45 years of age or older with RA and joint erosions by plain x-ray who are taking a biologic for at least three months and who have not taken more than two weeks of a bone active agent in the last 12 months will be eligible and screened for their interest in participating in the proposed randomized trial.

1. RA will be defined according to the 2010 American College of Rheumatology/European League Against Rheumatism diagnostic and classification criteria.

2. Osteopenic bone mineral density will be defined as a t-score between -1.0 and -2.5 on either a DXA of the PA or lateral lumbar spine or the femoral neck or total hip. Potential subjects with prior minimal trauma fractures will be excluded.

2.Subjects must be able to give written informed consent.

Exclusion Criteria:

1. A switch in DMARD in the last 3 months;

2. Current use of chronic oral glucocorticoids > 5 milligrams per day;

3. A prior history of intolerance to teriparatide;

4. T-score < -2.5 or a prior minimal trauma fracture;

5. Use of a bone active agent for over 2 weeks in the last 12 months (these agents include oral and intravenous bisphosphonates, hormone replacement therapy, calcitonin, raloxifene, teriparatide, suppressive doses of thyroxine, lithium, pharmacological doses of vitamin D (greater than 2000 IU/day or anticonvulsants);

6. History of significant cardiac, hepatic, current alcohol abuse, or major psychiatric disorders;

7. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematologic malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed within the previous 20 years;

8. No current diagnoses of disorders known to affect bone metabolism including hyperthyroidism, hyperparathyroidism, osteomalacia, or Paget's disease. All participants will be required to have normal serum levels of 25-OH vitamin D (> 20 ng/ml), intact PTH, and TSH. If PTH and/or 25-OH D levels are abnormal, subjects may be given calcium and/or multivitamin supplements and be re-tested in 2-12 weeks;

9. Serum Ca > 10.6 mg/dl,and 24-hour urine calcium > 400 mg. If minor abnormalities are detected in any of these parameters, the test may be repeated;

10. Patients who have had external beam radiation; and

11. Patients currently on digoxin.

12. Women that are currently pregnant or breast-feeding or plan on becoming pregnant over the course of participation in the study

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Teriparatide
20 mcg, subcutaneous injection, 1 injection per day

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Eli Lilly and Company

Country where clinical trial is conducted

United States, 

References & Publications (12)

Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, Kendler DL, Lentle B, Olszynski W, Ste-Marie LG, Tenenhouse A, Chines AA. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997 Aug 7;337(6):382-7. — View Citation

Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, Zizic TM, Wallach S, Sewell KL, Lukert BP, Axelrod DW, Chines AA. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 1999 Nov;42(11):2309-18. — View Citation

Cooper C, Coupland C, Mitchell M. Rheumatoid arthritis, corticosteroid therapy and hip fracture. Ann Rheum Dis. 1995 Jan;54(1):49-52. — View Citation

Eggelmeijer F, Papapoulos SE, van Paassen HC, Dijkmans BA, Valkema R, Westedt ML, Landman JO, Pauwels EK, Breedveld FC. Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial. Arthritis Rheum. 1996 Mar;39(3):396-402. — View Citation

Hall GM, Spector TD, Griffin AJ, Jawad AS, Hall ML, Doyle DV. The effect of rheumatoid arthritis and steroid therapy on bone density in postmenopausal women. Arthritis Rheum. 1993 Nov;36(11):1510-6. — View 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. — View Citation

Hooyman JR, Melton LJ 3rd, Nelson AM, O'Fallon WM, Riggs BL. Fractures after rheumatoid arthritis. A population-based study. Arthritis Rheum. 1984 Dec;27(12):1353-61. — View Citation

Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 1998 Oct 15;102(8):1627-33. — View Citation

Michel BA, Bloch DA, Wolfe F, Fries JF. Fractures in rheumatoid arthritis: an evaluation of associated risk factors. J Rheumatol. 1993 Oct;20(10):1666-9. — View Citation

Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States: effect of different methods of case classification. Arthritis Rheum. 2003 Apr;48(4):917-26. — View Citation

Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, Thamsborg G, Liberman UA, Delmas PD, Malice MP, Czachur M, Daifotis AG. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med. 1998 Jul 30;339(5):292-9. — View Citation

Spector TD, Hall GM, McCloskey EV, Kanis JA. Risk of vertebral fracture in women with rheumatoid arthritis. BMJ. 1993 Feb 27;306(6877):558. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Joint Erosion by 3D CT scan	Joint erosion scores, measured by 3D CT scan, will be significantly improved at study completion in patients taking teriparatide	12 months	No
Secondary	Lumbar by DXA	Teriparatide will significantly increase BMD at all sites as measured by DXA.	12 months	No

External Links

•   Brigham and Women's Clinical Trials