K1-70 - A Study in Subjects With Graves' Disease

Study Overview
=================
Brief Summary
-----------------
This study is the first time that K1-70 will be administered to humans. The principal aim of this study is to obtain safety and tolerability data when K1-70 is administered as an IM injection or as an IV infusion to subjects with Graves' disease. Current therapy for Graves' disease includes treatment with anti-thyroid drugs, destruction of the thyroid using radioiodine, or total surgical thyroidectomy. Beta-blockers and calcium antagonists may be used to control some of the symptoms of hyperthyroidism. K1-70 is a thyroid stimulating hormone receptor antagonist that may provide new in vivo diagnostic and therapeutic tools for the management of patients with Graves' disease, patients with thyroid cancer and patients who would benefit from controlling receptor activity.

Detailed Description
-----------------
Graves' disease is one of the most common overt autoimmune disorders. Patients with Graves' disease have thyroid over activity and hyperthyroidism. Symptoms of hyperthyroidism include goitre, fatigue, heat intolerance, sweating, weight loss despite good appetite, shakiness, inappropriate anxiety, palpitations of the heart, shortness of breath, tetchiness and agitation, poor sleep, thirst, nausea and increased frequency of defaecation. The rationale of this study is to obtain safety and tolerability data when K1-70 is administered as an intramuscular injection or as an IV infusion to subjects with Graves' disease. This information, together with the pharmacokinetic data, will help establish the doses and dosage regimen suitable for repeat administration to patients. This is an open-label study. The expected duration of each subject's participation in the study is approximately 18 weeks (including a screening period of up to 4 weeks).

Official Title
-----------------
K1-70 - A Phase I, Single Ascending Intramuscular Dose or Single Ascending Intravenous Dose, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study in Subjects With Graves' Disease

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

Intervention / Treatment
-----------------
* Drug: K1-70 intramuscular or K1-70 intravenous


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: age 18-75 years have Graves' disease and are being treated with anti-thyroid medications OR not treated with anti-thyroid medications (due to side-effects) and who are clinically and biochemically euthyroid or hyperthyroid have a body mass index (weight [kg]/height [m]2) between 18.5 and 35.0 kg/m2 Main Exclusion Criteria: current or chronic history of liver disease history of cancer within the last 5 years except localised skin cancer Graves' orbitopathy with clinical activity score >3/7 evidence of optic neuropathy and/or corneal breakdown significant systemic infection history of recurrent or current infection splenectomy recently had major surgery or plan major surgery had thromboembolic event due to a blood clot in the last 12 months have clinically significant laboratory tests a clinically significant allergic condition (excluding hay fever) currently receiving corticosteroids smoke more than 10 cigarettes (or its equivalent in nicotine (including use of e-cigarettes)) per day history of drug abuse

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: Single dose<br>The intervention is K1-70 intramuscular or K1-70 intravenous. This is a single, ascending, intramuscular or intravenous dose, sequential group study. | Drug: K1-70 intramuscular or K1-70 intravenous<br>* Each subject will receive one dose of K1-70 by IM injection or one dose of K1-70 by IV infusion on the morning of Day 1.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability will be measured using vital signs, ECG, blood samples for haematology, coagulation, clinical biochemistry and hormone panel, urinalysis, eye examinations, physical examinations and examination of injection or infusion site. | Safety and tolerability testing consists of vital signs, ECG, blood samples for haematology, coagulation, clinical biochemistry and hormone panel, urine samples for urinalysis, eye examinations, physical examinations and examination of injection or infusion site. All clinically significant results and the number of treatment related adverse events will be reported. | Over a period of 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The concentration of K1-70 drug in the blood will be measured over time. | The terminal elimination rate constant will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | The terminal elimination half life will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | Time of the maximum observed plasma concentration will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | Maximum observed plasma concentration will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | Area under the plasma concentration time curve to the last quantified concentration will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | Area under the plasma concentration time curve from time zero to infinity will be calculated and reported | Over a period of 18 weeks | 
| The concentration of K1-70 drug in the blood will be measured over time. | Percentage of area under the plasma concentration time curve that is extrapolated will be calculated and reported | Over a period of 18 weeks | 
| The antidrug antibodies will be measured to evaluate the immunogenic potential of K1-70 in Graves' disease patients | The level of antidrug antibodies present in the patient serum will be measured over time and reported. | Over a period of 18 weeks | 
| The effect of a single IM dose or single IV dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time | TSH levels will be measured and reported over time. | Over a period of 18 weeks | 
| The effect of a single IM dose or single IV dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time | Free T3 levels will be measured and reported over time. | Over a period of 18 weeks | 
| The effect of a single IM dose or single IV dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time | Free T4 levels will be measured and reported over time. | Over a period of 18 weeks |