A Study of Two Doses of MRC375 in Moderate to Severe Rheumatoid Arthritis Patients

This is a double-blind, randomized, placebo-controlled study to assess the safety and
efficacy of MRC375 at 75 mg or 150 mg with matching placebo (taken tid with meal or light
snack) in patients with moderate to severe RA. Patients will be randomized to one of the
following study arms for 24 weeks:

- Treatment 1, Placebo: 2 tablets taken tid

- Treatment 2, MRC375: 1 tablet of 75 mg tetracycline HCL plus 1 matching placebo tablet
taken tid. Total daily dose = 225 mg.

- Treatment 3, MRC375: 2 tablets of 75 mg tetracycline HCL taken tid. Total daily dose =
450 mg.

Study medication should be taken within 30 minutes of a meal or light snack (either before
or after).

Inclusion Criteria:

1. Is 18 years of age

2. Is diagnosed with moderate to severe adult onset RA > = 6 months duration, as defined
by the 1987 ACR classification criteria

3. Has moderate to severe RA as defined by:

- ≥4 tender joints/painful (28 joint count) at screening

- ≥4 swollen joints (28 joint count) at screening

4. Has a Health Assessment Questionnaire (HAQ) of >0

5. Has a physician global assessment (Likert scale) of >0

6. Has a patient global assessment of pain (Likert scale) of >0

7. Has a patient assessment of pain (Likert scale) of >0

8. Has stable doses of the following allowable medications during the study, if
applicable:

- Stable dose of NSAIDs or other analgesics for at least 2 weeks prior to
administration of study drug at regulatory approved doses

- Stable dose of methotrexate 7.5 mg to 25 mg/day once weekly for at least 6 weeks
prior to administration of study drug (no changes in dosing regimen for 4 weeks
prior to screening)

- Stable dose of hydroxychloroquine either monotherapy or in combination with
methotrexate 8 weeks prior to administration of study drug

9. Is a non-pregnant, non-lactating female who is postmenopausal, naturally or
surgically sterile, or who agree to use effective contraceptive methods throughout
the course of the study. Postmenopausal is defined as at least 12 months natural
spontaneous amenorrhea

10. If female of childbearing potential, must agree to use one of the following
acceptable birth control methods:

- Surgically sterile (bilateral tubal ligation with surgery at least 6 weeks prior
to screening, hysterectomy, or bilateral oophorectomy);

- Intrauterine device (IUD) in place for at least 3 months prior to first dose of
study drug;

- Abstinence (not having sexual intercourse);

- Barrier method (condom or diaphragm) with spermicide for at least 14 days prior
to screening and through study completion;

- Stable hormonal contraceptive for at least 3 months prior to study and through
study completion

11. If female of childbearing potential, has a negative serum hCG pregnancy test at
screening

12. Is able to swallow whole tablets of orally administered medication

13. Is able to understand and provide signed informed consent.

Exclusion Criteria:

1. Has been diagnosed with any other inflammatory arthritis (eg, psoriatic arthritis)

2. Has a secondary type of arthritis (eg, osteoarthritis) that would interfere with
study evaluations

3. Has taken the following drugs within the timeframe specified below:

- Infliximab, etanercept, adalimumab, abatacept, or other biological therapies
(except rituximab) - Within 12 weeks prior to the administration of study drug;

- Rituximab - Within 12 months prior to the administration of study drug;

- Disease-modifying antirheumatic drugs (DMARDs) or other anti-rheumatic therapies
not specified above including but not limited to: sulfasalazine, gold,
leflunomide, penicillamine, dapsone, azathioprine, 6-mercaptopurine,
chlorambucil, cyclophosphamide, cyclosporin, mycophenolate mofetil - Within 12
weeks prior to the administration of study drug;

- Any steroids (glucocorticoids); glucocorticoids must be discontinued for at
least 4 weeks prior to administration of study drug. Intraarticular,
intramuscular, or intravenous glucocorticoids must not have been given at least
6 weeks prior to administration of study drug.

- Note: Use of probiotics is allowed and is NOT an exclusion criterion.

4. Has a uncontrolled symptoms of fibromyalgia with sufficient symptoms requiring
treatment (NOTE: patients on a stable dose of treatment for symptoms of fibromyalgia
≥ 4 weeks will be allowed in the study.)

5. Has a history of allergic reaction to tetracycline or other related drugs

6. Had major surgery or trauma within 28 days prior to screening

7. Is concurrently using minocycline or doxycycline (washout of 4 weeks required before
the administration of study drug)

8. Patients who are on chronic antibiotics or who are on antibiotics for GI infections
(such as Clostridium difficile)

9. Has clinically significant ECG abnormalities

10. Has any clinically significant abnormal laboratory test results found during medical
screening including: AST or ALT > 2 x upper limit of normal or serum creatinine > 2.0
mg/dL

11. Has clinically significant history or presence of any gastrointestinal pathology (eg,
chronic diarrhea, inflammatory bowel disease, acute diverticulitis), irritable bowel
syndrome, unresolved gastrointestinal symptoms (eg. diarrhea, vomiting, symptoms of
acute diverticulitis), liver or kidney disease, gastric bypass, gastric stapling, use
of Lap-Band®, or other conditions known to or which might interfere with the
absorption, distribution, metabolism, or excretion of the drug

12. Has any historical or active neurological, endocrine, cardiovascular, pulmonary,
hematological, psychiatric, or metabolic disease that is considered clinically
significant by the Investigator

13. Has known history of HIV, hepatitis B or C (patients that have positive hepatitis B
serology due to prior vaccination will be allowed in the study)

14. Has an active malignancy of any type or history of malignancy. Patients who have a
history of a successfully treated non-metastatic cutaneous squamous cell or basal
cell carcinoma (ie. non melanoma skin cancer)and/or localized carcinoma in situ of
the cervix are eligible. Patients with a history of other malignancies that have been
treated and who have no evidence of recurrence for at least 5 years before study
enrollment are also eligible.

15. Has difficulty swallowing tablets

16. Is ACR Functional Class IV (limited ability to perform usual self-care, vocational,
and avocational activities)

17. Has known or suspected pregnancy, planned pregnancy, or lactation (for female
patients)

18. Has clinically significant mental illness (to be determined by the Investigator)

19. Has a history in the last 2 years or current evidence of abuse of illicit drugs,
prescription medications, or alcohol that, in the opinion of the Investigator, would
interfere with adherence to study requirements. Has exposure to any investigational
agent within 30 days prior to study entry.

20. Was previously enrolled in this study

21. Has recent history of bacterial intestinal tract infection (gastroenteritis, colitis,
diverticulitis, appendicitis)

22. Has a condition the Investigator believes would interfere with the ability to provide
informed consent or comply with study instructions, or that might confound the
interpretation of the study results or put the patient at undue risk