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

Rheumatoid Arthritis Clinical Trial

Official title:

Phase 1 Trial of CII APL A12 in Rheumatoid Arthritis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01123655
• Other study ID #: IMMA-007-08S
• Status: Completed
• Phase: Phase 1
• Start date: October 2009
• Est. completion date: September 2015

Study information

• Verified date: December 2018
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• APLA12
Intervention: Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.
• Placebo
Drug treatment will be stopped or interrupted if indicated. Medical care will be provided at no cost to the patient.

Locations

Country	Name	City	State
United States	Memphis VA Medical Center, Memphis, TN	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Laboratory Results of A12 vs Placebo Anti-CCP Antibody		0-16 weeks
Secondary	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
Secondary	Modified Health Assessment Questionnaire (MHAQ)	Modified Health Assessment Questionnaire (MHAQ) 0-8 with 8 being the most activity	0-16 weeks
Secondary	Duration of Morning Stiffness in Joints	Duration of morning stiffness in the joints, in minutes.	0-16 weeks
Secondary	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
Secondary	Vital Signs-Temperature		0-16 weeks
Secondary	Vital Sign - Pulse	heartbeats per minute	0-16 weeks
Secondary	Weight	Weight in kg	0-16 weeks
Secondary	Vitals - Blood Pressure	measurement of blood pressure (mmHg)	0 weeks and 16 weeks
Secondary	Vitals - Respirations	Respirations represents breaths per minute	0 weeks and 16 weeks