ATX-GD-59 in Patients With Graves Disease Not Treated With Anti-thyroid Therapy

Study Overview
=================
Brief Summary
-----------------
Phase 1 study to assess the safety and biological activity of ATX-GD-59 in patients with Graves Disease not currently treated with anti-thyroid therapy. This will be an open label dose titration involving injections on 10 occasions, each two weeks apart. After dosing is complete there will be a 12 week follow up period. Blood samples will be drawn throughout the study to monitor safety and the body's response to the injections. Thyroid function will be measured throughout the trial to monitor Graves disease progression.

Official Title
-----------------
Safety and Proof of Principle Study of ATX-GD-59 in Male and Female Subjects With Graves' Disease Not Currently Treated With Anti-thyroid Therapy: An Open Label Study, With an Upward Titration Over Five Dose Levels Administered by Intradermal Injection

Conditions
-----------------
Graves Disease

Intervention / Treatment
-----------------
* Biological: ATX-GD-59


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of Graves' disease as assessed by a physician from clinical and laboratory findings and not receiving anti-thyroid therapy. Quantifiable levels of TSHR antibodies. Raised levels of free T3 and/or free T4 (not exceeding 15 pmol/L and 35 pmol/L respectively) including undetectable levels of thyroid stimulating hormone. HLA-DRB1*15, HLA DRB1*03 and or HLA DRB1*04 positive. Age 18 - 65 years inclusive at the time of informed consent. The subject must be willing and able to give written informed consent and must be willing to comply with protocol assessments/procedures. Male subjects must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control for the duration of the study until at least 90 days after the last dose of ATX-GD-59. Female subjects of child bearing potential must: - neither be pregnant nor breast-feeding, nor attempting to conceive, and - use a highly effective method of contraception as defined below, throughout the entire duration of the study and for at least 90 days after the last dose of ATX-GD-59. A serum pregnancy test will be performed at the screening visit in women of child bearing potential. Thereafter urine pregnancy tests will be performed. A positive result will exclude the woman from the study immediately. A highly effective method of contraception is defined as those which result in a low failure rate when used consistently and correctly such as implants, injectable, combined oral contraceptives, some Intrauterine Devices (IUDs), unless post-menopausal or surgically sterilized. Barrier forms of contraception are considered appropriate when used in combination with one of the above methods. Exclusion Criteria: Subjects who are pregnant or breastfeeding and/or subjects in the post-partum period. A known history of, or hypersensitivity reactions that in the opinion of the investigator would exclude the subjects' participation in the study. Treatment with any Anti-Thyroid Drugs eg carbimazole within the previous 3 months prior to Study Day 1. Previous treatment with radioiodine or (partial or complete) thyroidectomy. Signs of moderate or severe orbitopathy including optic nerve compression requiring steroids and/or a clinical activity score >3. Large and compressive goitres causing localised symptoms such as difficulty swallowing or breathing. Treatment with steroids (administered via the oral and/or parenteral routes) or adrenocorticotropic hormone with the exception of inhaled steroids within the three months prior to Study Day 1. Symptoms and signs of thyroid storm such as confusion, pyrexia with no other cause than hyperthyroidism. Significant cardiac disease and/or atrial fibrillation that would require urgent treatment of thyrotoxicosis. Prior treatment with biological or peptide-based therapeutics including rituximab. Prior use of disease related T cell vaccine or peptide-tolerising agent to treat Graves' disease. Detectable levels of antibodies in plasma specific for any of the peptides within ATX-GD-59 at the screening visit. A history of significant drug allergies. The use of any investigational drug, or participation in any Clinical Trial within three months prior to Study Day 1. Treatment with any cytokine or anti-cytokine therapy within three months prior to Study Day 1. Inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 3 times the upper limit of the normal values at Screening visit. 17. Subject with any significant medical illness or psychiatric condition that in the opinion of the Investigator, would preclude participation in the study or impair the ability to give informed consent; any other clinically apparent autoimmune disease. 18. Clinically significant illness, as determined by the investigator, within 4 weeks prior to the first dose (Study Day 1) of ATX-GD-59. 19. Known history of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease, Latent or active TB, Hepatitis). 20. Major surgery in previous four weeks before screening visit. 21. Known osteoporosis or metabolic bone disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATX-GD-59 treatment<br>An upward titration over five dose levels (25, 50, 100, 400 and 800 micrograms) followed by 5 doses of 800 micrograms of ATX-GD-59 will be administered two weeks apart by intradermal injection. | Biological: ATX-GD-59<br>* Disease specific immune modulating treatment for Graves Disease<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline. | An adverse event (AE) was defined as any untoward medical occurrence in a subject administered study drug that did not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, disease or outcome of death temporally associated with the use of study drug, whether or not considered causally related to the study drug. Treatment emergent adverse events (TEAEs) were any AE that started or worsened in severity on or after the first administration of study drug up to and including 28 days after the last administration of study drug. Relationship, as indicated by the Investigator, was classified as 'not related', 'possibly related', 'probably related' or 'definitely related' (increasing severity of relationship). A drug related AE was defined as an AE with a relationship to study drug of 'possibly related', 'probably related' or 'definitely related' or with a missing or unknown relationship to study drug | 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by TSHR-binding Inhibitory Immunoglobulin (TBII) | TSHR-binding inhibitory immunoglobulin (TBII) are autoantibodies directed against the TSH receptor. TBII is used clinically for the differential diagnosis and management of Graves' Disease. | Weeks 18, 22 and 30 | 
| Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by Stimulatory TSHR Antibodies (TSAb) | Stimulatory TSHR antibodies (TSAb) assays were measured using cell-based methods described by Leschik et al. TSAb activity is measured by calculating percentage specimen-to-reference ratio (%SRR). | Weeks 18, 22 and 30 | 
| Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by Blocking TSHR Antibodies (TBAb) | Blocking TSHR antibodies (TBAb) assays were measured using cell-based methods described by Leschik et al. TBAb activity is measured by calculating percentage inhibition. | Weeks 18, 22 and 30 | 
| Change in Serum Free Triiodothyronine (fT3) From Baseline to Week 22. | Serum fT3 was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT3 value at study day 1. | Weeks 18, 22 and 30 | 
| Change in Serum Free Thyroxine (T4) From Baseline to Week 22. | Serum fT4 was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT4 value at study day 1. | Weeks 18, 22 and 30 | 
| Change in Serum Thyroid Stimulating Hormone (TSH) From Baseline to Week 22. | Serum TSH was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT4 value at study day 1. | Weeks 18, 22 and 30 | 
| Change From Baseline in Peripheral Blood Mononuclear Cell (PBMC) T Cell Activity |  | weeks 0, 18 and 22 | 
| Change From Baseline in IL-10 mRNA Expression in PBMCs |  | weeks 0, 18 and 22 | 
| Change From Baseline in Biomarker Signature of PBMC Cells |  | weeks 0, 18 and 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Graves Disease, Phase 1