Phase 1 Trial of CII APL A12 in Rheumatoid Arthritis Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Number and Percent of Participants With Reduction of Immunity to Collagen Type-II After APLA-12 Treatment.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Arm 1
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.
干预措施: APLA12 (Drug)
Arm 1
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.
干预措施: Placebo (Drug)
Arm 2
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.
干预措施: APLA12 (Drug)
Arm 2
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.
干预措施: Placebo (Drug)
Arm 3
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.
干预措施: APLA12 (Drug)
Arm 3
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Number and Percent of Participants With Reduction of Immunity to Collagen Type-II After APLA-12 Treatment.
时间窗: 16 weeks
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.
次要结局
- Hematocrit(0-16 weeks)
- Hemaglobin(Baseline and 16 weeks)
- Platelets(0-16 weeks)
- Duration of Morning Stiffness in Joints(0-16 weeks)
- Vital Sign - Pulse(0-16 weeks)
- Vitals - Respirations(0 weeks and 16 weeks)
- Change in Cytokine Profile From Baseline and 16 Weeks(0 and 16 weeks)
- Neutrophils Counts at 0 and 16 Weeks(Baseline and 16 weeks)
- Flow Cytometry(baseline and 8 or 16 weeks)
- Clinical Disease Activity Index (CDAI) at 0 and 16 Weeks Follow up(0 and16 weeks)
- Eosinophils(Baseline and 16 weeks)
- Laboratory Results of A12 vs Placebo: Basophils(Baseline and 16 weeks)
- Laboratory Results of A12 vs Placebo-Total Immunoglobulin (Immature Granulocytes)(Baseline and 16 weeks)
- White Blood Count(0-16 weeks)
- Change in IgG and IgA Immunoglobulin From Baseline to 8 or 16 Weeks(baseline and 8 or 16 wks)
- Laboratory Results of A12 vs Placebo: Lymphocytes(0-16 weeks)
- AST, ALT and Alkaline Phosphatase(0-16 weeks)
- Sodium, Potassium and Chloride(0-16 weeks)
- Rheumatoid Factor(0-16 weeks)
- Laboratory Results of A12 vs Placebo Anti-CCP Antibody(0-16 weeks)
- Patient Global Assessment (PGA) and Physician Global Assessment(0-16 weeks)
- Vital Signs-Temperature(0-16 weeks)
- A12 Treated vs Placebo of Monocytes.(Baseline and 16 wks)
- Red Blood Cell Distribution Width (RDW)(0 and 16 weeks)
- Red Blood Cells(0-16 weeks)
- Ca, BUN, Glucose,Creatinine, Total Bilirubin(0-16 weeks)
- Sedimentation Rate(0-16 weeks)
- Modified Health Assessment Questionnaire (MHAQ)(0-16 weeks)
- CDAI(0-16 weeks)
- Total Protein, Albumin(0-16 weeks)
- C-reactive Protein(0-16 weeks)
- Weight(0-16 weeks)
- Vitals - Blood Pressure(0 weeks and 16 weeks)