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

Study Description

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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 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.

Condition or disease	Intervention/treatment	Phase
Graves' Disease	Drug: K1-70 intramuscular	Phase 1

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 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).

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	36 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	K1-70 - A Phase I, Single Ascending Intramuscular Dose, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study in Subjects With Graves' Disease
Study Start Date :	July 2016
Estimated Primary Completion Date :	February 2020
Estimated Study Completion Date :	February 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Single dose; The intervention is K1-70 intramuscular. This is a single, ascending, intramuscular dose, sequential group study.	Drug: K1-70 intramuscular; Each subject will receive one dose of K1-70 by IM injection on the morning of Day 1.

Outcome Measures

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Primary Outcome Measures :

1. 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 site. [ Time Frame: Over a period of 18 weeks ]
   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 site. All clinically significant results and the number of treatment related adverse events will be reported.

Secondary Outcome Measures :

1. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   The terminal elimination rate constant will be calculated and reported
2. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   The terminal elimination half life will be calculated and reported
3. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   Time of the maximum observed plasma concentration will be calculated and reported
4. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   Maximum observed plasma concentration will be calculated and reported
5. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   Area under the plasma concentration time curve to the last quantified concentration will be calculated and reported
6. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   Area under the plasma concentration time curve from time zero to infinity will be calculated and reported
7. The concentration of K1-70 drug in the blood will be measured over time. [ Time Frame: Over a period of 18 weeks ]
   Percentage of area under the plasma concentration time curve that is extrapolated will be calculated and reported
8. The antidrug antibodies will be measured to evaluate the immunogenic potential of K1-70 in Graves' disease patients [ Time Frame: Over a period of 18 weeks ]
   The level of antidrug antibodies present in the patient serum will be measured over time and reported.
9. The effect of a single IM dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time [ Time Frame: Over a period of 18 weeks ]
   TSH levels will be measured and reported over time.
10. The effect of a single IM dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time [ Time Frame: Over a period of 18 weeks ]
    Free T3 levels will be measured and reported over time.
11. The effect of a single IM dose of K1-70 on thyroid activity in subjects with Graves' will be measured over time [ Time Frame: Over a period of 18 weeks ]
    Free T4 levels will be measured and reported over time.

Other Outcome Measures:

1. Exploratory Objective: Thyroid hormones will be measured over time and their correlation to baseline TSH receptor autoantibody (TRAb) levels will be reported at different time points [ Time Frame: Over a period of 18 weeks ]
   TSH levels will be reported against baseline TRAb over time.
2. Exploratory Objective: Thyroid hormones will be measured over time and their correlation to baseline TSH receptor autoantibody (TRAb) levels will be reported at different time points [ Time Frame: Over a period of 18 weeks ]
   Free T3 levels will be reported against baseline TRAb over time.
3. Exploratory Objective: Thyroid hormones will be measured over time and their correlation to baseline TSH receptor autoantibody (TRAb) levels will be reported at different time points [ Time Frame: Over a period of 18 weeks ]
   Free T4 levels will be reported against baseline TRAb over time.
4. Exploratory Objective: The potential effect of K1-70 on Graves' ophthalmopathy will be measured by eye examinations using the Clinical Activity Score (CAS) system. [ Time Frame: Over a period of 18 weeks ]
   All clinically significant results and the number of treatment related adverse events will be reported.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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) per day
• history of drug abuse

Contacts and Locations

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Contacts

Contact: MEU	+44 (0)161 946 4050	304@meu.org.uk

Locations

United Kingdom
Royal Liverpool University Hospital Clinical Research Unit	Recruiting
Liverpool, United Kingdom, L7 8XP
Contact: LCRU +44 (0)151 706 4863 CRU.contact@rlbuht.nhs.uk
Principal Investigator: Richard Fitzgerald, MD
Medicines Evaluation Unit	Recruiting
Manchester, United Kingdom, M23 9QZ
Contact: Dave Singh, Professor +44 (0)161 946 4050 dsingh@meu.org.uk

Sponsors and Collaborators

AV7 Limited

Investigators

Principal Investigator:	Dave Singh, Professor	Medicines Evaluation Unit, Manchester, UK

More Information

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Publications:

Evans M, Sanders J, Tagami T, Sanders P, Young S, Roberts E, Wilmot J, Hu X, Kabelis K, Clark J, Holl S, Richards T, Collyer A, Furmaniak J, Smith BR. Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrinol (Oxf). 2010 Sep;73(3):404-12. doi: 10.1111/j.1365-2265.2010.03831.x. Epub 2010 Jun 9.

Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Núñez Miguel R, Furmaniak J, Rees Smith B. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J Mol Endocrinol. 2011 Feb 15;46(2):81-99. doi: 10.1530/JME-10-0127. Print 2011 Apr.

Furmaniak J, Sanders J, Young S, Kabelis K, Sanders P, Evans M, Clark J, Wilmot J, Rees Smith B. In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70). Auto Immun Highlights. 2011 Sep 14;3(1):19-25. doi: 10.1007/s13317-011-0025-9. eCollection 2012 Apr.

Responsible Party:	AV7 Limited
ClinicalTrials.gov Identifier:	NCT02904330 History of Changes
Other Study ID Numbers:	K1im001
First Posted:	September 16, 2016
Last Update Posted:	May 18, 2018
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Graves Disease; Exophthalmos; Orbital Diseases; Eye Diseases; Goiter	Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases