Teriparatide for Joint Erosions in Rheumatoid Arthritis: The TERA Trial

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.

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