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

Primary Purpose

Graves' Disease

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
K1-70 intramuscular or K1-70 intravenous
Sponsored by
AV7 Limited
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graves' Disease

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Royal Liverpool University Hospital Clinical Research Unit
  • Medicines Evaluation Unit

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single dose

Arm Description

The intervention is K1-70 intramuscular or K1-70 intravenous. This is a single, ascending, intramuscular or intravenous dose, sequential group study.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

The concentration of K1-70 drug in the blood will be measured over time.
The terminal elimination rate constant will be calculated and reported
The concentration of K1-70 drug in the blood will be measured over time.
The terminal elimination half life will be calculated and reported
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
The concentration of K1-70 drug in the blood will be measured over time.
Maximum observed plasma concentration will be calculated and reported
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
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
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
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.
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.
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.
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.

Full Information

First Posted
August 18, 2016
Last Updated
May 18, 2021
Sponsor
AV7 Limited
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1. Study Identification

Unique Protocol Identification Number
NCT02904330
Brief Title
K1-70 - A Study in Subjects With Graves' Disease
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
August 2016 (Actual)
Primary Completion Date
April 2021 (Actual)
Study Completion Date
April 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AV7 Limited

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graves' Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Single dose
Arm Type
Experimental
Arm Description
The intervention is K1-70 intramuscular or K1-70 intravenous. This is a single, ascending, intramuscular or intravenous dose, sequential group study.
Intervention Type
Drug
Intervention Name(s)
K1-70 intramuscular or K1-70 intravenous
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
Over a period of 18 weeks
Secondary Outcome Measure Information:
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
The terminal elimination rate constant will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
The terminal elimination half life will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
Time of the maximum observed plasma concentration will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
Maximum observed plasma concentration will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
Area under the plasma concentration time curve to the last quantified concentration will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
Area under the plasma concentration time curve from time zero to infinity will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The concentration of K1-70 drug in the blood will be measured over time.
Description
Percentage of area under the plasma concentration time curve that is extrapolated will be calculated and reported
Time Frame
Over a period of 18 weeks
Title
The antidrug antibodies will be measured to evaluate the immunogenic potential of K1-70 in Graves' disease patients
Description
The level of antidrug antibodies present in the patient serum will be measured over time and reported.
Time Frame
Over a period of 18 weeks
Title
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
Description
TSH levels will be measured and reported over time.
Time Frame
Over a period of 18 weeks
Title
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
Description
Free T3 levels will be measured and reported over time.
Time Frame
Over a period of 18 weeks
Title
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
Description
Free T4 levels will be measured and reported over time.
Time Frame
Over a period of 18 weeks
Other Pre-specified Outcome Measures:
Title
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
Description
TSH levels will be reported against baseline TRAb over time.
Time Frame
Over a period of 18 weeks
Title
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
Description
Free T3 levels will be reported against baseline TRAb over time.
Time Frame
Over a period of 18 weeks
Title
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
Description
Free T4 levels will be reported against baseline TRAb over time.
Time Frame
Over a period of 18 weeks
Title
Exploratory Objective: The potential effect of K1-70 on Graves' ophthalmopathy will be measured by eye examinations using the Clinical Activity Score (CAS) system.
Description
All clinically significant results and the number of treatment related adverse events will be reported.
Time Frame
Over a period of 18 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dave Singh, Professor
Organizational Affiliation
Medicines Evaluation Unit, Manchester, UK
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal Liverpool University Hospital Clinical Research Unit
City
Liverpool
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Medicines Evaluation Unit
City
Manchester
ZIP/Postal Code
M23 9QZ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
20550534
Citation
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.
Results Reference
background
PubMed Identifier
21247981
Citation
Sanders P, Young S, Sanders J, Kabelis K, Baker S, Sullivan A, Evans M, Clark J, Wilmot J, Hu X, Roberts E, Powell M, Nunez 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.
Results Reference
background
PubMed Identifier
26000124
Citation
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.
Results Reference
background

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

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