Phase 1 Trial of Type II Collagen (CII) APL A12 in Rheumatoid Arthritis Patients

Study Overview
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Brief Summary
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This is a Phase I clinical trial to determine whether orally administered APL A12 at one or more doses is superior to placebo in effecting a 25% reduction in interferon (IFN) stimulation index in 1(II)-stimulated culture of peripheral blood mononuclear (PBMC) obtained from patients with Rheumatoid Arthritis (RA), which will be the primary outcome variable. In an effort to learn more about the mechanism of action of APL A12, the investigators will assess Th1/Th2/Th3 cytokine production in supernatants from 48h and 144h cultures of PBMC stimulated by 1(II) and by APL A12 above. The investigators will assess function of CD4+ CD25+ T regs to determine whether APL A12 improves their suppressive function. Flow cytometry combined with intracellular cytokine staining will be used in an effort to determine which T cell subset(s) is/are experiencing shifts in cytokine expression.

Detailed Description
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The study will have 3 treatment arms each with 10 patients who have demonstrated T cell immunity to CII and have an in vitro response to APL A12 at the screening visit. Patients will be randomized to one of the 3 treatment arms. Each of the 3 treatments will be given for 16 weeks. In keeping with a sequential dose escalation strategy, the originally proposed randomization scheme will be modified so that subjects will be randomized to receive either the lowest dose (30 mg) or placebo (Block 1), followed by the next dose (50 mg) or placebo (Block 2). We will begin with the lowest dose (30 g/day) and enroll 6 to receive 30 g/day APL A12 and 2 to receive placebo for 16 weeks. Results will be reported to the Data Monitoring Committee (DMC) for a decision to proceed to the next block based on indications of safety. If this dose does not cause adverse events or toxicity or worsens RA, we will proceed to enroll patients to receive 30 ug, or 50 g/day APL A12 or placebo for 16 weeks. A total of 32 subjects will be randomized to obtain 24 subjects who complete the study. Recruitment was difficult. Only 22 patients were randomized. There were not enough 50mcg patients enrolled so 2 treatment groups was analyzed. Arm 1 included 30 and 50 mcg and Arm 2 represents the patients that received placebo.

Official Title
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Phase 1 Trial of CII APL A12 in Rheumatoid Arthritis Patients

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: APLA12
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet the following criteria for participation in the study. Male or female; age > 18 years. American College of Rheumatology (ACR) 1988 revised criteria for rheumatoid arthritis. Onset of disease age 16 or older. Onset of disease at least 3 months prior to enrollment. RA patients ages 18-85 with RA of 3 month duration which in the opinion of the examining rheumatologist is clinically stable and will likely not require adjustment of doses of Disease-modifying antirheumatic drugs (DMARDS), NSAIDS, prednisone, anti-tumor necrosis factor (anti-TNF) alpha therapies for the 16 weeks of the treatment phase of the study. Patients must agree to discontinue all herbal remedies as described in this protocol. Women of childbearing age will be advised to use effective means of contraception for the treatment phase of the trial and for 90 days thereafter. They must have a negative urine pregnancy test at the randomization visit. (Required by the FDA.) Men will be advised to use effective means of contraception for the treatment phase of the trial and for 90 days thereafter. (Required by the FDA.) Crohn's Disease Activity Index (CDAI) less than or equal to 30 at the baseline visit. Patients with a past history of malignant neoplasm will be eligible if they are 1 or greater years with no recurrence of malignant neoplasm. Exclusion Criteria: Inability to render an informed consent in accordance with institutional guidelines. Participation in another clinical research study involving the evaluation of another investigational drug within 90 days of entry into this study. RA patients on >7.5 mg prednisone a day. RA patients with intra-articular corticosteroid injections during the previous 30 days. Concurrent serious medical condition which in the opinion of the investigator makes the patient inappropriate for the study. Hepatitis B abd/or C patients with inactive disease (as determined by PI) will be enrolled. Positive urine pregnancy test Age 85 years or greater. Use of fish oil within the previous 4 weeks of the baseline visit. Therapy consisting of auranofin or cyclophosphamide (all other DMARDs are allowed). Previous autologous or heterologous stem cell transplantation. Active malignant neoplasm or past treatment for malignant neoplasm 1 year from screening visit. Use of oral CII within the past 1 year. (Since oral tolerance is short-lived, we will permit patients in the study who have been off oral CII for > 1 year) Diabetes requiring insulin or on oral medications must be well managed at baseline. Adjustment of insulin or on oral medications will be allowed during the study. Serum creatinine 2.0 mcg/dL. An 1(II) IFN value <100% of the PBS IFN value within 1 month or less prior to the baseline and less than 25% reduction in APL A12 + 1(II) IFN from 1(II) IFN concentration. CDAI > 30 at the baseline visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>The study will have 3 treatment arms each with 10-12 patients who have demonstrated T cell immunity to CII and have an in vitro response to APL A12 at the screening visit. Patients will be randomized to one of the 2 treatment arms (30 micrograms APL A12 or placebo). Each of the 2 treatments will be given for 16 weeks. Intervention: Drug treatment will be stopped or interrupted if indicated and medical care will be given as appropriate. Intervention: Drug treatment will be stopped or interrupted if indicated and medical care will be given as appropriate. | Drug: APLA12<br>* Intervention: Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>Drug: Placebo<br>* Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>|
| Experimental: Arm 2<br>The next group will receive a higher dose (50 micrograms) and/or placebo (Block 2). Intervention: Drug treatment will be stopped or interrupted if indicated and medical care will be given as appropriate. | Drug: APLA12<br>* Intervention: Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>Drug: Placebo<br>* Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>|
| Experimental: Arm 3<br>Block 3 (Arm 3) will include placebo and both doses of APL/A12 to ensure 10-12 patients are enrolled in each arm ( total of approximately 32 subjects) so we will have 24 subjects who complete the 16 weeks of study treatment. Arms 2 and 3 will run simultaneously. Intervention: Drug treatment will be stopped or interrupted if indicated. | Drug: APLA12<br>* Intervention: Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>Drug: Placebo<br>* Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percent of Participants With Reduction of Immunity to Collagen Type-II After APLA-12 Treatment. | The primary outcome variable is the presence of a > 25% reduction in net IFN concentration in supernatants of 1(II)-stimulated PBMC cultures from baseline after 16 weeks of treatment. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow Cytometry | Change in Percentage of CD4+CD25+FoxP3 T regulatory cells, CD4+IL-10+ cells, CD4+ IL-4+ cells, CD4+IL17+ cells. Some patients had only had enough blood collected at 8 weeks or 16 weeks or dropped out after 8 weeks, and we used/combined what was available. | baseline and 8 or 16 weeks | 
| Clinical Disease Activity Index (CDAI) at 0 and 16 Weeks Follow up | Interpretation of Clinical Disease Activity Index (CDAI) scores < 2.8 indicate remission; >2.8 and <= 10 indicates low disease activity; >10 and <= 22 indicates moderate disease activity; >22 indicates high disease activity. | 0 and16 weeks | 
| Change in Cytokine Profile From Baseline and 16 Weeks | Cytokines assessed are IL-10, IL-13, IL-5, IL-1B, IL-9, IL-17A, IL-6, IL-21, TGF-B, TNFa,and MIP3A. | 0 and 16 weeks | 
| Change in IgG and IgA Immunoglobulin From Baseline to 8 or 16 Weeks | The change was computed between baseline and 8 or 16 weeks, whichever was available. | baseline and 8 or 16 wks | 
| Neutrophils Counts at 0 and 16 Weeks | Laboratory Results of A12 vs Placebo:Complete blood count Neutrophil count to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 weeks | 
| A12 Treated vs Placebo of Monocytes. | Laboratory Results of A12 treated vs Placebo of Monocytes to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 wks | 
| Eosinophils | Laboratory Results of A12 treated vs Placebo of Eosinophils to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 weeks | 
| Laboratory Results of A12 vs Placebo: Lymphocytes | Measure to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Laboratory Results of A12 vs Placebo: Basophils | Measure to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 weeks | 
| Hematocrit | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Laboratory Results of A12 vs Placebo-Total Immunoglobulin (Immature Granulocytes) | Measure to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 weeks | 
| Red Blood Cell Distribution Width (RDW) | Laboratory Results of A12 vs Placebo RDW is a measure of the range of variation of red blood cell volume reported as part of a standard blood count to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0 and 16 weeks | 
| Hemaglobin | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | Baseline and 16 weeks | 
| Red Blood Cells | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| White Blood Count | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Platelets | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| AST, ALT and Alkaline Phosphatase | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Ca, BUN, Glucose,Creatinine, Total Bilirubin | Laboratory Results of A12 vs Placebo-CMP to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Sodium, Potassium and Chloride | Laboratory results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Total Protein, Albumin | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| C-reactive Protein | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Rheumatoid Factor | Laboratory Results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Sedimentation Rate | Laboratory results of A12 vs Placebo to determine whether APL has any effect on routine blood counts, chemistries, electrolytes, immunoglobulin to measure potential toxicities | 0-16 weeks | 
| Laboratory Results of A12 vs Placebo Anti-CCP Antibody |  | 0-16 weeks | 
| Patient Global Assessment (PGA) and Physician Global Assessment | Patient and Physician (PI) Assessments both range from 0-10 with 10 being the most disease activity | 0-16 weeks | 
| Modified Health Assessment Questionnaire (MHAQ) | Modified Health Assessment Questionnaire (MHAQ) 0-8 with 8 being the most activity | 0-16 weeks | 
| Duration of Morning Stiffness in Joints | Duration of morning stiffness in the joints, in minutes. | 0-16 weeks | 
| CDAI | Clinical Disease Activity Index (CDAI) 0-76 mm. Interpretation of CDAI scores < 2.8 indicate remission; >2.8 and <= 10 indicates low disease activity; >10 and <= 22 indicates moderate disease activity; >22 indicates high disease activity. | 0-16 weeks | 
| Vital Signs-Temperature |  | 0-16 weeks | 
| Vital Sign - Pulse | heartbeats per minute | 0-16 weeks | 
| Weight | Weight in kg | 0-16 weeks | 
| Vitals - Blood Pressure | measurement of blood pressure (mmHg) | 0 weeks and 16 weeks | 
| Vitals - Respirations | Respirations represents breaths per minute | 0 weeks and 16 weeks |