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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02973802

Enrollment

Registered

2016-11-25

Start date

2016-09-30

Completion date

2018-02-14

Last updated

2019-06-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Graves Disease

Keywords

Graves Disease, Phase 1

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.

Interventions

BIOLOGICALATX-GD-59

Disease specific immune modulating treatment for Graves Disease

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

1. A diagnosis of Graves' disease as assessed by a physician from clinical and laboratory findings and not receiving anti-thyroid therapy. 2. Quantifiable levels of TSHR antibodies. 3. 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. 4. HLA-DRB1\*15, HLA DRB1\*03 and or HLA DRB1\*04 positive. 5. Age 18 - 65 years inclusive at the time of informed consent. 6. The subject must be willing and able to give written informed consent and must be willing to comply with protocol assessments/procedures. 7. 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. 8. 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

1. Subjects who are pregnant or breastfeeding and/or subjects in the post-partum period. 2. A known history of, or hypersensitivity reactions that in the opinion of the investigator would exclude the subjects' participation in the study. 3. Treatment with any Anti-Thyroid Drugs eg carbimazole within the previous 3 months prior to Study Day 1. 4. Previous treatment with radioiodine or (partial or complete) thyroidectomy. 5. Signs of moderate or severe orbitopathy including optic nerve compression requiring steroids and/or a clinical activity score \>3. 6. Large and compressive goitres causing localised symptoms such as difficulty swallowing or breathing. 7. 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. 8. Symptoms and signs of thyroid storm such as confusion, pyrexia with no other cause than hyperthyroidism. 9. Significant cardiac disease and/or atrial fibrillation that would require urgent treatment of thyrotoxicosis. 10. Prior treatment with biological or peptide-based therapeutics including rituximab. 11. Prior use of disease related T cell vaccine or peptide-tolerising agent to treat Graves' disease. 12. Detectable levels of antibodies in plasma specific for any of the peptides within ATX-GD-59 at the screening visit. 13. A history of significant drug allergies. 14. The use of any investigational drug, or participation in any Clinical Trial within three months prior to Study Day 1. 15. Treatment with any cytokine or anti-cytokine therapy within three months prior to Study Day 1. 16. 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.

Design outcomes

Primary

Measure	Time frame	Description
Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	22 weeks	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

Secondary

Measure	Time frame	Description
Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by Stimulatory TSHR Antibodies (TSAb)	Weeks 18, 22 and 30	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).
Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by Blocking TSHR Antibodies (TBAb)	Weeks 18, 22 and 30	Blocking TSHR antibodies (TBAb) assays were measured using cell-based methods described by Leschik et al. TBAb activity is measured by calculating percentage inhibition.
Change in Serum Free Triiodothyronine (fT3) From Baseline to Week 22.	Weeks 18, 22 and 30	Serum fT3 was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT3 value at study day 1.
Change in Serum Free Thyroxine (T4) From Baseline to Week 22.	Weeks 18, 22 and 30	Serum fT4 was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT4 value at study day 1.
Change in Serum Anti-TSHR Antibodies From Baseline to Week 22 - Measured by TSHR-binding Inhibitory Immunoglobulin (TBII)	Weeks 18, 22 and 30	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.
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	—
Change in Serum Thyroid Stimulating Hormone (TSH) From Baseline to Week 22.	Weeks 18, 22 and 30	Serum TSH was measured centrally from screening to the final week 30 follow-up visit. Baseline was fT4 value at study day 1.

Countries

United Kingdom

Participant flow

Recruitment details

This study enrolled patients diagnosed with Graves Disease from 8 hospital clinics located in the UK. The last patient enrolled completed dosing in February 2018.

Pre-assignment details

28 subjects were screened for the study, of which 12 were eligible, and commenced treatment with ATX-GD-59.

Participants by arm

Arm	Count
ATX-GD-59 Treatment 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 administered two weeks apart by intradermal injection. ATX-GD-59: Disease specific immune modulating treatment for Graves Disease	12
Total	12

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	ATX-GD-59 Treatment
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	12 Participants
Age, Continuous	42.7 years STANDARD_DEVIATION 9.69
Race/Ethnicity, Customized Asian	1 Participants
Race/Ethnicity, Customized White	11 Participants
Sex: Female, Male Female	11 Participants
Sex: Female, Male Male	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 12
other Total, other adverse events	11 / 12	4 / 12
serious Total, serious adverse events	1 / 12	0 / 12

Outcome results

Primary

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

Time frame: 22 weeks

Population: The Intention-to-treat population corresponded to all subjects who received at least 1 administration of study drug at any time during the study, irrespective of compliance with eligibility and other protocol criteria. The Safety population was denoted as the 'Intention-to-treat population' for the summarisation of safety endpoints.

Arm	Measure	Group	Value (NUMBER)
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Total Adverse Events	311 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Mild Adverse Events	293 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Moderate Adverse Events	18 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Severe Adverse Events	0 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Drug Related Adverse Events	180 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Total Serious Adverse Events	3 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Drug Related Serious Events	1 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Adverse Events leading to death	0 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Adverse Events leading to early study withdrawal	0 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Events leading to dose interruption or suspension	0 Adverse Events
ATX-GD-59 Treatment	Occurrence of Treatment Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Laboratory Abnormalities up to Week 22 Compared to Baseline.	Treatment emergent injection related reaction	153 Adverse Events

Secondary

Change From Baseline in Biomarker Signature of PBMC Cells

Time frame: weeks 0, 18 and 22

Population: No clear treatment effects could be determined possibly due to technical issues with the preparation and assay of the PBMCs. In addition, the 2 week post dose time point of blood sampling, meant that the induced Treg cells or cytokine changes were no longer detectable in peripheral blood.

Secondary

Change From Baseline in IL-10 mRNA Expression in PBMCs

Time frame: weeks 0, 18 and 22

Secondary

Change From Baseline in Peripheral Blood Mononuclear Cell (PBMC) T Cell Activity

Time frame: weeks 0, 18 and 22

Secondary

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.