sPIF CLINICAL STUDY PROTOCOL IN AUTOIMMUNE HEPATITIS

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability and Pharmacokinetics of Synthetic PreImplantation Factor (sPIF) in Autoimmune Hepatitis

The purpose of this study is to study the safety and tolerability of synthetic PreImplantation Factor (sPIF) in female patients with autoimmune hepatitis. Autoimmune hepatitis is a disease where the patient's immune system produces an inappropriate immune response against their own liver. PreImplantation Factor is a substance that is secreted by viable fetuses during pregnancy. PIF apparently initiates both maternal tolerance preventing the loss/rejection of the fetus. Synthetic PIF (sPIF) successfully translates PIF endogenous properties to pregnant and non-pregnant immune disorders. sPIF was found to be effective in preclinical models of autoimmunity and transplantation (published). Specifically sPIF protected the liver against immune attack. Toxicity studies (mice, dogs) have shown that high-dose sPIF administration for 2 weeks followed by 2 weeks observation period demonstrated a high safety profile. This study will evaluate the safety, tolerability and the blood level of this synthetic version of this natural compound in the circulation.

Study Overview

• Status: Completed
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Drug: Placebo; Drug: sPIF

Detailed Description

Both sPIF as well as natural PIF appears to orchestrate a complex series of cytokine effects that overall appear to cause return of proper immune function and regulation rather than a nonspecific immune suppression. PIF acts on both the innate and adaptive arms of the immune system in a dynamic, diverse and synergetic manner "per need". In the pregnancy setting, PIF maintains basal immunity required for embryo and maternal survival, and aids in tolerance for self by blocking activated T cells proliferation that would otherwise harm the embryo. The activity of PIF appears to have a dual complementary mode of action that is dependent on whether the immune system is in the basal or the stimulated immune state. The sPIF concentrations that were used are in the same range as those that are present in maternal circulation of viable pregnancy. sPIF targets three major intracellular proteins that pivotal in autoimmune control.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Center for Liver Diseases; University of Miami
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003-3157
      • Chief Scientist, BIOINCEPT, LLC / Chairman, (SIEP) / Director, Ob&Gyn CAMcare Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female, aged from 18 to 70 years old, of non-child bearing potential (to avoid the possibility if antibodies are formed to sPIF this could put the patient at risk for future fertility)

• Females must be either

  • Postmenopausal for greater than two years,
  • Postmenopausal for less than two years with an follicle stimulating hormone (FSH) level greater > 40 million international units per milliliter (mIU/mL )
  • Or documented as surgically sterile (bilateral tubal ligation, bilateral oophorectomy or post-hysterectomy) at least three months prior to the screening evaluation

• Autoimmune hepatitis as documented by a:

  • Pretreatment score ≥15
  • Or a post-treatment score of ≥17 on the International Criteria for the Diagnosis of Autoimmune Hepatitis (Appendix 2)
• Treatment with prednisone and/or other oral, immunosuppressive drug(s) must have been stabilized for at least 6 weeks prior to screening for this study.
• Stable ALT levels with a fixed dose of their immunosuppressant medications
• Subjects do not have to have had a documented relapse after completion of an initial course of therapy

• Permitted concomitant immunosuppressant medications will include

  • Azathioprine dose equal to/or less 100 mg per day,
  • Budesonide dose equal to/or less 9 mg per day,
  • Mycophenolate mofetil equal to/or less 3000 mg per day,
  • Prednisone equal to/or less than 10 mg per day
  • Ursodeoxycholic acid equal to/or less than 1000 mg per day
• In the judgment of the Investigator, be in reasonable general health, based on review of the results of a screening evaluation (to include physical examination, measurement of vital signs, 12-lead ECG trace and the collection of blood and urine for routine clinical laboratory testing), performed no more than 30 days prior to Day 1 of study.
• Patients must agree to abstain from alcohol use during their participation in the study protocol.
• Alanine aminotransferase (ALT) levels of no more than five times the upper limit of normal (reference) range (ULN) at the screening evaluation.
• Normal renal function as determined by a serum creatinine
• A female of childbearing potential who is documented as either surgically sterile (bilateral tubal ligation, bilateral oophorectomy or post-hysterectomy at least 3 months prior to the screening evaluation) or post-menopausal for ≥ 2 years.

Exclusion Criteria:

• Any other forms of chronic liver disease.
• Decompensated liver disease defined on the basis of any one of the following laboratory parameters at the screening evaluation: total bilirubin > 1.5 × ULN, prothrombin time > 1.2 × ULN, platelets ≤ 100,000/mm3, or albumin < 3 g/dL OR current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy or variceal hemorrhage).
• Hemoglobin < 11 g/dL at the screening evaluation.
• Serological evidence of infection with HIV upon review of the medical record.
• Evidence of hepatocellular carcinoma (i.e., screening α-fetoprotein > 50 ng/mL or other standard of care measure).
• Subjects with, or a history of clinically significant oncologic, pulmonary, hepatic, gastrointestinal, renal, other cardiovascular, hematologic, metabolic, endocrine, neurologic, immunologic or hematologic illness or any other major medical disorder that, in the judgment of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol or should otherwise preclude their participation in this trial.
• Have received therapy with potentially hepatotoxic drugs within 3 months (90 days) prior to Day 1 or are expected to receive such therapy during the study.
• Patient who are expected to receive a change in their immunosuppressant therapies during the protocol.
• Patients who may receive chemotherapeutic agents (e.g., corticosteroids, immunoglobulins and other immune- or cytokine-based therapies) during the study for any other medical condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAD sPIF 0.1; single ascending dose (SAD) 3 patients with normal liver function tests (LFTs) and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) as follows: Single subcutaneous (SQ) dose 0.1 mg/kg sPIF or Placebo Day 1	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor
Experimental: SAD sPIF 0.5; single ascending dose (SAD) 3 patients with normal LFTs and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) as follows: single SQ dose 0.5 mg/kg sPIF or Placebo Day 1	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor
Experimental: SAD sPIF 1.0; single ascending dose (SAD) 3 patients with normal LFTs and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) as follows: Cohort 3: single SQ dose 1.0 mg/kg sPIF or Placebo Day 1	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor
Experimental: MAD sPIF 0.1; multiple ascending dose (MAD) 3 patients with normal LFTs and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) to multiple doses of sPIF SQ (one time) 1X day for 5 consecutive days (Days 1 to 5) Cohort 1: SQ 0.1 mg/kg sPIF or Placebo Days 1-5	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor
Experimental: MAD sPIF 0.5; multiple ascending dose (MAD) 3 patients with normal LFTs and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) to multiple doses of sPIF SQ 1X day for 5 consecutive days (Days 1 to 5) Cohort 1: SQ 0.5 mg/kg sPIF or Placebo Days 1-5	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor
Experimental: MAD sPIF 1.0; multiple ascending dose (MAD) 3 patients with normal LFTs and 3 patients with abnormal LFTs randomized in a 2:1 ratio (active drug:placebo) to multiple doses of sPIF SQ 1X day for 5 consecutive days (Days 1 to 5) Cohort 1: SQ 1.0 mg/kg sPIF or Placebo Days 1-5	Drug: Placebo; Other Names: Ringer's lactated solution; Drug: sPIF; Other Names: synthetic PreImplantation Factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety/Tolerability Measured by Clinical Laboratory Tests, Metabolics, Cytokines, Anti-PIF Antibody, Periodic Physical Examination, Including Vital Signs Measurements and 12-lead ECG	Single Ascending Dose (SAD): Adverse events, concomitant medications: Days 1, 2, 3, 5, 8 Vital signs, Physical exams: Days 1, 2, 8 Complete blood counts (CBC), Serum chemistry, Liver function tests, Pharmacokinetics: Days 1, 2, 8 Lipids, Coagulation, Urinalysis, Pregnancy test: Days 1, 8 EKG, chest x-ray (CXR): Days 1 and 8 Multiple Ascending Dose (MAD): Adverse events, concomitant medications: Days 1, 2, 3, 4, 5, 8, 15, 29 Vital signs, Physical exams: Days 1, 2, 3, 4, 5, 8, 15, 29 CBC, Serum chemistry, Liver function tests, Pharmacokinetics: Days 1, 3, 5, 8, 15, 29 Lipids, Coagulation, Urinalysis, Pregnancy test, EKG: Days 1, 5, 29 CXR: Days 1, 29	29 Day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Anti-sPIF Antibodies and Drug Interactions	Following sPIF administration, using a validated assay, serum samples were tested for anti-sPIF antibodies	29 Day

Collaborators and Investigators

• Sponsor: Christopher O'Brien, MD
• Collaborators: BioIncept LLC
• Investigators: Principal Investigator: Christopher B. O'Brien, MD, University of Miami

Publications and helpful links

General Publications

• Di Simone N, Di Nicuolo F, Marana R, Castellani R, Ria F, Veglia M, Scambia G, Surbek D, Barnea E, Mueller M. Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response. PLoS One. 2017 Jul 12;12(7):e0180642. doi: 10.1371/journal.pone.0180642. eCollection 2017.
• Barnea ER, Vialard F, Moindjie H, Ornaghi S, Dieudonne MN, Paidas MJ. PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress. J Reprod Immunol. 2016 Apr;114:58-64. doi: 10.1016/j.jri.2015.06.002. Epub 2015 Jul 21.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2014
• Primary Completion (Actual): April 25, 2016
• Study Completion (Actual): December 29, 2016

Study Registration Dates

• First Submitted: September 10, 2014
• First Submitted That Met QC Criteria: September 10, 2014
• First Posted (Estimate): September 12, 2014

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: October 30, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Hepatitis; Liver; Autoimmune; sPIF; synthetic PreImplantation Factor
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Immune System Diseases; Autoimmune Diseases; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis, Autoimmune
• Other Study ID Numbers: 20140114; 119219 (Registry Identifier: FDA IND Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: There is no plan to share with other researchers.